HETEROCYCLIC COMPOUNDS AS PI3K-y INHIBITORS

ABSTRACT

This application relates to compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts or stereoisomers thereof, which are inhibitors of PI3K-γ which are useful for the treatment of disorders such as autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/589,523, filed Oct. 1, 2019, which is a divisional of U.S.application Ser. No. 16/045,358, filed Jul. 25, 2018, which is acontinuation of U.S. application Ser. No. 15/343,375, filed Nov. 4,2016, which claims the benefit of U.S. Ser. No. 62/252,050, filed Nov.6, 2015, the disclosure of which is incorporated herein by reference inits entirety.

FIELD OF THE INVENTION

The present invention provides heterocyclic compounds that modulate theactivity of phosphoinositide 3-kinases-gamma (PI3Kγ) and are useful inthe treatment of diseases related to the activity of PI3Kγ including,for example, autoimmune diseases, cancer, cardiovascular diseases, andneurodegenerative diseases.

BACKGROUND

The phosphoinositide 3-kinases (PI3Ks) belong to a large family of lipidsignaling kinases that phosphorylate phosphoinositides at the D3position of the inositol ring (Cantley, Science, 2002,296(5573):1655-7). PI3Ks are divided into three classes (class I, II,and III) according to their structure, regulation and substratespecificity. Class I PI3Ks, which include PI3Kα, PI3Kβ, PI3Kγ, andPI3Kδ, are a family of dual specificity lipid and protein kinases thatcatalyze the phosphorylation of phosphatidylinosito-4,5-bisphosphate(PIP₂) giving rise to phosphatidylinosito-3,4,5-trisphosphate (PIP₃).PIP₃ functions as a second messenger that controls a number of cellularprocesses, including growth, survival, adhesion and migration. All fourclass I PI3K isoforms exist as heterodimers composed of a catalyticsubunit (p110) and a tightly associated regulatory subunit that controlstheir expression, activation, and subcellular localization. PI3Kα,PI3Kβ, and PI3Kδ associate with a regulatory subunit known as p85 andare activated by growth factors and cytokines through a tyrosinekinase-dependent mechanism (Jimenez, et al., J Biol Chem., 2002,277(44):41556-62) whereas PI3Kγ associates with two regulatory subunits(p101 and p84) and its activation is driven by the activation ofG-protein-coupled receptors (Brock, et al., J Cell Biol., 2003,160(1):89-99). PI3Kα, and PI3Kβ are ubiquitously expressed. In contrast,PI3Kγ and PI3Kδ are predominantly expressed in leukocytes(Vanhaesebroeck, et al., Trends Biochem Sci., 2005, 30(4):194-204).

Expression of PI3Kγ is mainly restricted to hematopoietic system,although it can be also detected at lower level in endothelium, heartand brain. PI3Kγ knock-out or kinase dead knock in mice are normal andfertile and do not present any overt adverse phenotypes. Analysis at thecellular level indicates that PI3Kγ is required for GPCR ligand-inducedPtdINs (3,4,5)P3 production, chemotaxis and respiratory burst inneutrophils. PI3Kγ-null macrophages and dendritic cell exhibit reducedmigration towards various chemoattractants. T-cells deficient in PI3Kγshow impaired cytokine production in response to anti-CD3 or Con Astimulation. PI3Kγ working downstream of adenosine A3A receptor iscritical for sustained degranulation of mast cells induced by FCϵRIcross-linking with IgE. PI3Kγ is also essential for survival ofeosinophils (Ruckle et al., Nat. Rev. Drug Discovery, 2006, 5, 903-918)

Given its unique expression pattern and cellular functions, thepotential role of PI3Kγ in various autoimmune and inflammatory diseasemodels has been investigated with genetic and pharmacological tools. Inasthma and allergy models, PI3Kγ^(−/−) mice or mice treated with PI3Kγinhibitor showed a defective capacity to mount contact hypersensitivityand delayed-type hypersensitivity reactions. In these models, PI3Kγ wasshown to be important for recruitment of neutrophils and eosinopohils toairways and degranulation of mast cells (see e.g. Laffargue et al.,Immunity, 2002, 16, 441-451; Prete et al., The EMBO Journal, 2004, 23,3505-3515; Pinho et al., L. Leukocyte Biology, 2005, 77, 800-810; Thomaset al., Eur. J. Immunol. 2005, 35, 1283-1291; Doukas et al., J.Pharmacol. Exp Ther. 2009, 328, 758-765).

In two different acute pancreatitis models, genetic ablation of PI3Kγsignificantly reduced the extent of acinar cell injury/necrosis andneutrophil infiltration without any impact on secretive function ofisolated pancreatic acini (Lupia et al., Am. J. Pathology, 2004, 165,2003-2011). PI3Kγ^(−/−) mice were largely protected in four differentmodels of rheumatoid arthritis (CIA, α-CII-IA, K/BxN serum transfer andTNF transgenic) and PI3Kγ inhibition suppressed the progression of jointinflammation and damage in the CIA and α—CII-IA models (see e.g., Campset al., Nat. Medicine, 2005, 11, 939-943; Randis et al., Eur. J.Immunol, 2008, 38, 1215-1224; Hayer et al., FASB J., 2009, 4288-4298).In the MRL-lpr mouse model of human systemic lupus erythematous,inhibition of PI3Kγ reduced glomerulonephritis and prolonged life span(Barber et al., Nat. Medicine, 2005, 9, 933-935).

There is evidence suggesting that chronic inflammation due toinfiltration by myeloid-derived cells is a key component in theprogression of neurodegeneration diseases, such as Alzheimer's disease(AD) (Giri et al., Am. J. Physiol. Cell Physiol., 2005, 289, C264—C276;El Khoury et al., Nat. Med., 2007, 13, 432-438). In line with thissuggestion, PI3Kγ inhibition was shown to attenuate Aβ(1-40)-inducedaccumulation of activated astrocytes and microglia in the hippocampusand prevent the peptide-induced congnitive deficits and synapticdysfunction in a mouse model of AD (Passos et al., Brain Behay. Immun.2010, 24, 493-501). PI3Kγ deficiency or inhibition also was shown todelay onset and alleviate symptoms in experimental autoimmuneencephalomyelitis in mice, a mouse model of human multiple sclerosis,which is another form of neurodegeneration disease (see e.g., Rodrigueset al., J. Neuroimmunol. 2010, 222, 90-94; Berod et al., Euro. J.Immunol. 2011, 41, 833-844; Comerford et al., PLOS one, 2012, 7, e45095;Li et al., Neuroscience, 2013, 253, 89-99).

Chronic inflammation has been formally recognized as one of thehallmarks for many different types of cancers. Accordingly, selectiveanti-inflammatory drugs represent a novel class of anti-cancer therapies(Hanahan and Weinberg, Cell, 2011, 144, 646-674). Since PI3Kγ isreported to mediate various inflammatory processes, its role as animmune oncology target has also been investigated. A recent studyreported that PI3Kγ deficiency suppressed tumor growth in the syngeneicmodels of lung cancer, pancreatic cancer and melanoma (LLC, PAN02 andB16). PI3Kγ deficiency or inhibition also inhibited tumor growth in aspontaneous breast cancer model (Schmid et al., Cancer Cell, 2011, 19,715-727). A further study reported that PI3Kγ deficiency couldameliorate inflammation and tumor growth in mice havingcolitis-associated colon cancer, (Gonzalez-Garcia et al.,Gastroenterology, 2010, 138, 1373-1384). Detailed mechanistic analysisindicates that tumor infiltration by CD11b⁺ myeloid cells can causeprotumorigenic inflammation at tumor sites and PI3Kγ in the myeloidcells is critical in mediating signaling of various chemoattractants inbring the cells to the tumor (Schmid et al., Cancer Cell, 2011, 19,715-727). Other studies suggest that PI3Kγ is also required fordifferentiation of naïve myeloid cells into M2 macrophges at tumorsites. M2 macrophages promote tumor growth and progression by secretingimmunosuppressive factors such arginase 1, which depletes the tumormicroenvironment of arginine, thereby promoting T-cell death and NK cellinhibition (Schmidt et al., Cancer Res. 2012, 72 (Suppl 1: Abstract,411; Kaneda et al., Cancer Res., 74 (Suppl 19: Abstact 3650)).

In addition to its potential role in promoting protumorigenicmicroenvironment, PI3Kγ may play a direct role in cancer cells. PI3Kγ isreported to be required for signaling from the Kaposi'ssarcoma-associated herpevirus encoded vGPCR oncogene and tumor growth ina mouse model of sarcoma (Martin et al., Cancer Cell, 2011, 19,805-813). PI3Kγ was also suggested to be required for growth of T-ALL(Subramanjam et al., Cancer Cell, 2012, 21, 459-472), PDAC and HCC cells(Falasca and Maffucci, Frontiers in Physiology, 2014, 5, 1-10).Moreover, in a survey of driver mutations in pancreatic cancer, PI3Kγgene was found to contain second highest scoring predicted drivenmutation (R839C) among the set of genes not previously identified as adriver in pancreatic cancer (Carteret al., Cancer Biol. Ther. 2010, 10,582-587).

Finally, PI3Kγ deficiency also has been reported to offer protection toexperimental animals in different cardiovascular disease models. Forexamples, lack of PI3Kγ would reduce angiotension-evoked smooth musclecontraction and, therefore, protect mice from angiotension-inducedhypertension (Vecchione et al., J. Exp. Med. 2005, 201, 1217-1228). Inrigorous animal myocardial infarction models, PI3Kγ inhibition providedpotent cardioprotection, reducing infarct development and preservingmyocardial function (Doukas et al., Proc. Natl. Acad. Sci. USA, 2006,103, 19866-19871).

For these reasons, there is a need to develop new PI3Kγ inhibitors thatcan be used for the treatment of diseases such as cancer, autoimmunedisorders, and inflammatory and cardiac diseases. This application isdirected to this need and others.

SUMMARY

The present invention related to, inter alfa, compounds of Formula (I):

or pharmaceutically acceptable salts, wherein constituent members aredefined herein.

The present invention further provides pharmaceutical compositionscomprising a compound of Formula I, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

The present invention further provides methods of inhibiting an activityof PI3Kγ kinase comprising contacting the kinase with a compound ofFormula I, or a pharmaceutically acceptable salt thereof.

The present invention further provides methods of treating a disease ora disorder associated with abnormal PI3Kγ kinase expression or activityin a patient by administering to a patient a therapeutically effectiveamount of a compound of Formula I, or a pharmaceutically acceptable saltthereof.

The present invention further provides a compound of Formula I, or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound of Formula I,or a pharmaceutically acceptable salt thereof, for the preparation of amedicament for use in any of the methods described herein.

DETAILED DESCRIPTION Compounds

The present application provides, inter alfa, a compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein:

X¹ and X² are each independently C or N, provided X¹ and X² are notsimultaneously N;

X³ is N, NR^(3a), or CR³;

X⁴ is N, NR^(4a), or CR⁴;

X⁵ is N, NR^(5a), or CR⁵;

W is CH or N;

Y¹ is N or CR¹⁰;

Y² is N or CR¹¹;

one of Z¹ and Z² is N, the other of Z¹ and Z² is C;

is a single bond or a double bond to maintain ring A and ring B beingaromatic;

R¹ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl or 4-10 membered heterocycloalkyl, wherein C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and 4-10membered heterocycloalkyl are each optionally substituted with 1, 2 or 3independently seleted R^(j) substituents;

R² is OR¹³, C₃₋₆ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,or 5-10 membered heteroaryl, wherein the C₃₋₆ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl of R² areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(j) substituents;

R³, R⁴, R⁵ and R⁶ are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(=NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R³, R⁴, R⁵, and R⁶ are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(b)substituents;

R^(3a), R^(4a), and R^(5a) are each independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), C(═NR^(a))R^(a),C(═NR^(a))NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), _(an)dS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(3a), R^(4a), and R^(5a) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(b)substituents;

R⁷ is selected from H, halo, CN, —OH, —C(O)O(C₁₋₄ alkyl), —C(O)NH₂,—C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, (C₁₋₄ alkyl)C(O)NH—, (C₁₋₄alkyl)C(O)—, C₁₋₄ alkylthio, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, —SO₂(C₁₋₄ alkyl),—SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, (C₁₋₄ alkyl)SO₂NH—, 4-10membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the—C(O)O(C₁₋₄ alkyl), —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, (C₁₋₄alkyl)C(O)NH—, (C₁₋₄ alkyl)C(O)—, C₁₋₄ alkylthio, —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, —SO₂(C₁₋₄ alkyl), —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂,(C₁₋₄ alkyl)SO₂NH—, 4-10 membered heterocycloalkyl, and 5-10 memberedheteroaryl groups of R⁷ are each optionally substituted with 1 or 2independently selected R^(q) substituents

R⁸, R⁹, R¹⁰ and R¹¹ are each independently H, halo, CN, —OH, —C(O)O(C₁₋₄alkyl), —C(O)NH₂, —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, (C₁₋₄alkyl)C(O)NH—, (C₁₋₄ alkyl)C(O)—, C₁₋₄ alkylthio, —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, —SO₂(C₁₋₄ alkyl), —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂,and (C₁₋₄ alkyl)SO₂NH—, wherein the —C(O)O(C₁₋₄ alkyl), —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄ alkyl)₂, (C₁₋₄ alkyl)C(O)NH—, (C₁₋₄ alkyl)C(O)-,C₁₋₄ alkylthio, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, —SO₂(C₁₋₄ alkyl), —SO₂NH(C₁₋₄alkyl), —SO₂N(C₁₋₄ alkyl)₂ and (C₁₋₄ alkyl)SO₂NH— groups of R⁸, R⁹, R¹⁰and R¹¹ are each optionally substituted with 1 or 2 independentlyselected R^(q) substituents;

each R¹² is an independently selected C₁₋₆ alkyl group;

R¹³ is H or C₁₋₆ alkyl optionally substituted with 1, 2 or 3independently selected R^(q) substituents;

each R^(a) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(d) substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(b)substituents;

each R^(b) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each furtheroptionally substituted with 1, 2, or 3 independently selected R^(d)substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedW substituents;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

each R^(d) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH₂,NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e),OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl ofR^(d) are each further optionally substituted with 1, 2, or 3independently selected R^(q) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 independently selected R^(n) substituents;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1, 2, or 3 independently selected R^(p)substituents;

each R^(h) is selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i), C(O)R^(i),C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i),NR^(i)R^(i), NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i),C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i),S(O)NR^(i)R^(i), S(O)₂R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)2NR^(i)R^(i),and S(O)2NR^(i)R^(i), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(h) are each furtheroptionally substituted with 1, 2, or 3 independently selected R^(j)substituents;

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they attach form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

each R^(j) substituent is independently selected from C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k), SR^(k),C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k),NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k), NR^(k)C(O)NR^(k)R^(k),NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k), NR^(k)C(═NR^(k))NR^(k)R^(k),S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k), NR^(k)S(O)₂R^(k),NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k);

each R^(n) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,halo, CN, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o),C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o),NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),and S(O)₂NR^(o)R^(o); and

each R^(e), R^(i), R^(k), R^(o) or R^(p) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, and 5 or 6-membered heteroaryl; wherein the C₁₋₄alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl of R^(e), R^(i), R^(k), R^(o) orR^(p) are each optionally substituted with 1, 2 or 3 independentlyselected R^(q) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; and

each R^(q) is independently selected from OH, CN, —COOH, NH₂, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, phenyl, 5-6 membered heteroaryl,C₃₋₆ cycloalkyl, NHR¹², NR¹²R¹², and C₁₋₄ haloalkoxy, wherein the C₁₋₄alkyl, phenyl and 5-6 membered heteroaryl of R^(q) are each optionallysubstituted with OH, CN, —COOH, NH₂, C₁₋₄ alkoxy, C₃₋₁₀ cycloalkyl, and4-6 membered heterocycloalkyl.

In some embodiments:

X¹ and X² are each independently C or N, provided X¹ and X² are notsimultaneously N;

X³ is N, NR^(3a), or CR³;

X⁴ is N, NR^(4a), or CR⁴;

X⁵ is N, NR^(5a), or CR⁵;

W is CH or N;

Y¹ is N or CR¹⁰;

Y² is N or CR¹¹;

one of Z¹ and Z² is N, the other of Z¹ and Z² is C;

is a single bond or a double bond to maintain ring A and ring B beingaromatic;

R¹ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl or 4-10 membered heterocycloalkyl, wherein C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and 4-10membered heterocycloalkyl are each optionally substituted with 1, 2 or 3independently seleted R^(j) substituents;

R² is OR¹³, C₃₋₆ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,or 5-10 membered heteroaryl, wherein the C₃₋₆ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl of R² areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedsubstituents;

R³, R⁴, R⁵ and R⁶ are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R³, R⁴, R⁵, and R⁶ are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(b)substituents;

R^(3a), R^(4a), and R^(5a) are each independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), C(═NR^(a))R^(a),C(═NR^(a))NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), _(an)dS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(3a), R^(4a), and R^(5a) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(b)substituents;

R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently H, halo, CN, —OH,—C(O)O(C₁₋₄ alkyl), —C(O)NH₂, —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂,(C₁₋₄ alkyl)C(O)NH—, (C₁₋₄ alkyl)C(O)—, C₁₋₄ alkylthio, —NH(C₁₋₄.alkyl), —N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, —SO₂(C₁₋₄ alkyl), —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂,and (C₁₋₄ alkyl)SO₂NH—, wherein the —C(O)O(C₁₋₄ alkyl), —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄ alkyl)₂, (C₁₋₄ alkyl)C(O)NH—, (C₁₋₄ alkyl)C(O)—,C₁₋₄ alkylthio, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, —SO₂(C₁₋₄ alkyl), —SO₂NH(C₁₋₄alkyl), —SO₂N(C₁₋₄alkyl)2 and (C₁₋₄ alkyl)SO₂NH— groups of R⁷, R⁸, R⁹,R¹⁰ and R¹¹ are each optionally substituted with 1 or 2 independentlyselected R^(q) substituents;

each R¹² is an independently selected C₁₋₆ alkyl group;

R¹³ is H or C₁₋₆ alkyl optionally substituted with 1, 2 or 3independently selected R^(q) substituents;

each R^(a) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(d) substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents;

each R^(b) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂,NHOR^(c), OR^(c), C(O)R^(c), C(O)NR^(c) R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c) )NR^(c)R^(c), NR^(c) C(═NR^(c))NR^(c) R^(c),NHR^(c), NR^(c)R^(c), NR^(c) C(O)R^(c), NR^(c) C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) andS(O)₂NR^(c)R^(c) ; wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each further optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(f) substituents;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

each R^(d) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH₂,NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e),OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl ofR^(d) are each further optionally substituted with 1, 2, or 3independently selected R^(q) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g)NR^(g)R^(g),NR^(g)C(═NR^(g)NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)2NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 independently selected RP substituents;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ arylC₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(g) are each optionally substituted with 1, 2, or 3 independentlyselected R^(p) substituents;

each R^(h) is selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i), C(O)R^(i),C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i),NR^(i)R^(i), NR^(i), C(O)R^(i), NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i),C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i),S(O)NR^(i)R^(i), S(O)₂R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i),and S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(h) are each furtheroptionally substituted with 1, 2, or 3 independently selected IVsubstituents;

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they attach form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

each R^(j) substituent is independently selected from C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k), SR^(k),C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k),NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k), NR^(k)C(O)NR^(k)R^(k),NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k), NR^(k)C(═NR^(k))NR^(k)R^(k),S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k), NR^(k)S(O)₂R^(k),NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k);

each R^(n) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,halo, CN, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o),C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o),NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o)NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),and S(O)₂NR^(o)R^(o); and

each R^(e), R^(i) , R^(k), R^(o) or R^(p) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, and 5 or 6-membered heteroaryl; wherein the C₁₋₄alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl of R^(e), R^(i), R^(k), R^(o) orR^(p) are each optionally substituted with 1, 2 or 3 independentlyselected R^(q) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; and

each R^(q) is independently selected from OH, CN, —COOH, NH₂, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, phenyl, 5-6 membered heteroaryl,C₃₋₆ cycloalkyl, NHR¹², NR¹²R¹², and C₁₋₄ haloalkoxy, wherein the C₁₋₄alkyl, phenyl and 5-6 membered heteroaryl of R^(q) are each optionallysubstituted with OH, CN, —COOH, NH₂, C₁₋₄ alkoxy, C₃₋₁₀ cycloalkyl, and4-6 membered heterocycloalkyl.

In some embodiments, X¹ is C; and X² is C.

In some embodiments, X¹ is N; and X² is C.

In some embodiments, X¹ is C; and X² is N.

In some embodiments, X³ is N.

In some embodiments, X³ is NR^(3a).

In some embodiments, X³ is CR³.

In some embodiments, X⁴ is N.

In some embodiments, X⁴ is NR^(4a).

In some embodiments, X⁴ is CR⁴.

In some embodiments, X⁵ is N.

In some embodiments, X⁵ is NR^(5a).

In some embodiments, X⁵ is CR⁵.

In some embodiments, W is CH.

In some embodiments, W is N.

In some embodiments, W is CH; X¹ is C; X² is N; X³ is CR³; X⁴ is N; andX⁵ is CR⁵.

In some embodiments, W is CH; X¹ is C; X² is C; X³ is NR^(3a); X⁴ is N;and X⁵ is CR⁵.

In some embodiments, W is CH; X¹ is C; X² is C; X³ is N; X⁴ is NR^(4a);and X⁵ is CR⁵.

In some embodiments, Y¹ is N.

In some embodiments, Y² is N.

In some embodiments, Z¹ is C; and Z² is N.

In some embodiments:

In some embodiments:

In some embodiments:

In some embodiments, R¹ is H, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl or C₁₋₆alkyl.

In some embodiments, R¹ is H or C₁₋₆ alkyl.

In some embodiments, R¹ is C₁₋₆ alkyl.

In some embodiments, R¹ is methyl, ethyl or 1-propyl.

In some embodiments, R¹ is methyl.

In some embodiments, R² is OR¹³, C₆₋₁₀ aryl, 5-10 memberedheterocycloalkyl, or 5-10 membered heteroaryl; wherein said C₆₋₁₀ aryl,5-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R² areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(j) substituents.

In some embodiments, R² is OR¹³, C₆₋₁₀ aryl, or 5-10 memberedheteroaryl; wherein said C₆₋₁₀ aryl or 5-10 membered heteroaryl of R²are each optionally substituted with 1, 2, 3, 4, or 5 independentlyselected R substituents.

In some embodiments, R² is OR¹³ or C₆₋₁₀ aryl; wherein said C₆₋₁₀ arylof R² is optionally substituted with 1, 2, or 3 independently selectedR^(j) substituents.

In some embodiments, R² is C_(h6) alkoxy, phenyl, or monocyclic 5-6membered heteroaryl; wherein said C₆₋₁₀ aryl or monocyclic 5-6 memberedheteroaryl of R² are each optionally substituted with 1, 2, or 3independently selected R^(j) substituents.

In some embodiments, R² is C₁₋₆ alkoxy or phenyl, wherein said phenyl ofR² is optionally substituted with 1, 2, or 3 independently selectedR^(j) substituents.

In some embodiments, R² is C₁₋₆ alkoxy, phenyl, 5-6 memberedheterocycloalkyl, or monocyclic 5-6 membered heteroaryl; wherein saidC₆₋₁₀ aryl, 5-6 membered heterocycloalkyl, monocyclic 5-6 memberedheteroaryl of R² are each optionally substituted with 1, 2, or 3independently selected R^(j) substituents.

In some embodiments, R² is 5-6 membered heterocycloalkyl which isoptionally substituted with 1, 2, or 3 independently selected R^(j)substituents.

In some embodiments, R² is 1,1-dioxidothiomorpholin-4-yl optionallysubstituted with 1 or 2 independently selected R^(j) substituents.

In some embodiments, R² is ethoxy, 1,1-dioxidothiomorpholino optionallysubstituted with 1 or 2 C₁₋₄ independently selected alkyl substituents,or phenyl optionally substituted with halo.

In some embodiments, R² is ethoxy or phenyl optionally substituted withhalo.

In some embodiments, R² is 1,1-dioxidothiomorpholino optionallysubstituted with 1 or 2 independently selected C₁₋₄ alkyl substituents.

In some embodiments, R² is 2-methyl-1,1-dioxidothiomorpholino.

In some embodiments, each R^(j) is independently selected from halo, CN,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, NHOR^(k),OR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), and S(O)₂NR^(k)R^(k).

In some embodiments, each R^(k) is independently selected from H, C₁₋₄alkyl, and C₁₋₄ haloalkyl.

In some embodiments, each R is independently selected from halo, CN,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄alkylamino, and di(C₁₋₄ alkyl)amino.

In some embodiments, each R^(j) is independently C₁₋₄ alkyl or halo.

In some embodiments, each R^(j) is independently C₁₋₄ alkyl.

In some embodiments, each R^(j) is independently methyl.

In some embodiments, each R^(j) is independently halo.

In some embodiments, R² is ethoxy, phenyl, or 3-fluorophenyl.

In some embodiments, R^(3a) is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-;wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(3a) are each optionally substitutedby 1, 2, 3, or 4 independently selected R^(b) substituents.

In some embodiments, R^(3a) is H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, phenyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl,and (4-6 membered heterocycloalkyl)-C₁₋₄ alkyl; wherein said C₁₋₆ alkyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl, and (4-6 membered heterocycloalkyl)-C₁₋₄ alkylof R^(3a) are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(b) substituents. In some embodiments, each R^(b) isindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, OH,NH₂, NHOR^(c), OR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), NHR^(c), NHR^(c), NR^(c)R^(c),NR^(c)C(O)R^(c), NR^(c)(O)OR^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c). In some embodiments, each R^(b) isindependently selected from C₁₋₄ alkyl, OH, OR^(c), CN, C(O)NR^(c)R^(c),and NR^(c)R^(c). In some embodiments, each R^(c) is independentlyselected from H and C₁₋₆ alkyl.

In some embodiments, R^(3a) is H, methyl, isopropyl, isobutyl,—CH₂C≡CCH₃, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CN, —CH₂CH₂NH₂, —CH₂C(O)NH₂,benzyl, cyclobutyl, —CH₂-(1methyl1H-pyrazol-3-yl), or—CH₂CH₂-(morpholin-4-yl).

In some embodiments, R³ is H, halo, CN, C₁₋₆ alkyl, or C₁₋₆ haloalkyl.

In some embodiments, R³ is H or C₁₋₆ alkyl.

In some embodiments, R³ is H, methyl, or ethyl.

In some embodiments, R^(4a) is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-;wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(4a) are each optionally substitutedby 1, 2, 3, or 4 independently selected R^(b) substituents.

In some embodiments, R^(4a) is selected from H, C₁₋₆ alkyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, phenyl-C₁₋₄ alkyl-, and (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₁₋₆ alkynyl, C₃₋₁₀cycloalkyl, phenyl-C₁₋₄ alkyl-, and (5-6 membered heteroaryl)-C₁₋₄alkyl- of R^(4a) are each optionally substituted by 1, 2, 3, or 4independently selected R^(b) substituents.

In some embodiments, R^(4a) is selected from H, C₁₋₆ alkyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, and (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl and (4-10 memberedheteroaryl)-C₁₋₄ alkyl- of R^(4a) are each optionally substituted by 1,2, 3, or 4 independently selected R^(b) substituents.

In some embodiments, each R^(b) is independently selected from halo,C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, OH, NH₂, NHOR^(c), OR^(c), C(O)R^(c),C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), NHR^(c)C,NR^(c)R^(c), NR^(c)(O)R^(c), NR^(c) C(O)OR^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), S(O)₂R^(c) and S(O)₂NR^(c) R^(c). In some embodiments,each R^(b) is independently selected from C₁₋₄ alkyl, OH, OR^(c), CN,NR^(c)R^(c), and C(O)NR^(c) R^(c). In some embodiments, each R^(c) isindependently H or C₁₋₆ alkyl; or any two R^(c) substituents togetherwith the nitrogen atom to which they are attached form a 4-, 5-, 6-, or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents.

In some embodiments, R^(4a) is H, methyl, ethyl, isopropyl, isobutyl,—CH₂C≡CCH₃, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CN, —CH₂CH₂NH₂, cyclobutyl,benzyl, —CH₂C(O)NH₂, —CH₂-(1-methyl-1H-pyrazol-3-yl), or—CH₂C(O)-(morpholin-4-yl).

In some embodiments, R⁴ is selected from H, halo, CN, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR⁴ are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(b) substituents.

In some embodiments, R⁴ is selected from H, halo, CN, C₁₋₆ alkyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, phenyl-C₁₋₄ alkyl-, and (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₁₋₆ alkynyl, C₃₋₁₀cycloalkyl, phenyl-C₁₋₄ alkyl-, and (5-6 membered heteroaryl)-C₁₋₄alkyl- of R⁴ are each optionally substituted by 1, 2, 3, or 4independently selected R^(b) substituents.

In some embodiments, R⁴ is H, halo, CN, C₁₋₆ alkyl, or C₁₋₆ haloalkyl.

In some embodiments, R⁴ is H or C₁₋₆ alkyl.

In some embodiments, R⁵ is H, halo, C₁₋₆ alkyl, or C₁₋₆ haloalkyl.

In some embodiments, R⁵ is H, halo, or C₁₋₆ alkyl.

In some embodiments, R⁵ is H, bromo, chloro, fluoro, methyl, ethyl,n-propyl, or isopropyl.

In some embodiments, R⁵ is H, bromo, or methyl.

In some embodiments, R⁶ is H, halo, CN, C₁₋₆ alkyl, or C₁₋₆ haloalkyl.

In some embodiments, R⁶ is halo, CN, or C₁₋₆ alkyl.

In some embodiments, R⁶ is selected from chloro, CN, and methyl.

In some embodiments, R⁷ is H, 4-10 membered heterocycloalkyl, or 5-10membered heteroaryl, wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl are each optionally substituted with 1 or 2independently selected R^(q) substituents.

In some embodiments, R⁷ is H, 5-6 membered heterocycloalkyl, or 5-6membered heteroaryl, wherein the 5-6 membered heterocycloalkyl and 5-6membered heteroaryl are each optionally substituted with 1 or 2independently selected R^(q) substituents.

In some embodiments, R⁷ is H, piperidinyl, or pyridyl, wherein thepiperidinyl and pyridyl groups are each optionally substituted with 1 or2 independently selected R^(q) substituents.

In some embodiments, R⁷ is H, piperidinyl, or pyridyl, wherein thepiperidinyl and pyridyl groups are each optionally substituted with 1 or2 groups independently selected from C₁₋₄ alkyl and C₁₋₄ alkoxy, whereinthe C₁₋₄ alkyl group is optionally substituted by OH.

In some embodiments, R⁷ is H, piperidin-1-yl, or pyridin-3-yl, whereinthe piperidin-1-yl and piperidin-3-yl groups are each optionallysubstituted with 1 or 2 groups independently selected from C₁₋₄ alkyland C₁₋₄ alkoxy, wherein the C₁₋₄ alkyl group is optionally substitutedby OH.

In some embodiments, R⁷, R⁸, and R⁹ are each H.

In some embodiments:

R¹ is H or C₁₋₆ alkyl;

R² is 5-6 membered heterocycloalkyl optionally substituted with 1, 2 or3 independently selected R^(j) substituents;

each R^(j) is independently selected from halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, NHOR^(k), OR^(k), C(O)R^(k),C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k),NR^(k)R^(k), NR^(k)C(O)R^(k), S(O)₂R^(k), NR^(k)S(O)₂R^(k), andS(O)₂NR^(k)R^(k);

R^(3a) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(3a) are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(b)substituents;

R^(4a) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(4a) are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(b)substituents;

R³ is H or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is H, halo, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R^(5a) is H or C₁₋₆ alkyl;

R⁶ is H, halo, CN, C₁₋₆ alkyl, or C₁₋₆ haloalkyl; and

R⁷ is H, halo, CN, C₁₋₆ alkyl, or C₁₋₆ haloalkyl.

In some embodiments:

R¹ is C₁₋₆ alkyl;

R² is 5-6 membered heterocycloalkyl, wherein said 5-6 memberedheterocycloalkyl of R² is optionally substituted with 1 or 2independently selected R substituents;

each R is independently C₁₋₄ alkyl;

R^(3a) is H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl, and (4-6 memberedheterocycloalkyl)-C₁₋₄ alkyl; wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,phenyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl, and (4-6membered heterocycloalkyl)-C₁₋₄ alkyl of R^(3a) are each optionallysubstituted by 1, 2, 3, or 4 independently selected R^(b) substituents;

R^(4a) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl-C₁₋₄ alkyl-, and (5-6 membered heteroaryl)-C₁₋₄ alkyl-; whereinsaid C₁₋₆ alkyl and (5-6 membered heteroaryl)-C₁₋₄ alkyl- of R^(4a) areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(b) substituents;

R³ is H or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R^(5a) is H or C₁₋₆ alkyl;

R⁵ is H, halo, or C₁₋₆ alkyl;

R⁶ is halo, CN, or C₁₋₆ alkyl;

each R^(b) is independently selected from C₁₋₄ alkyl, OH, OR^(c), CN,and NR^(c)R^(c), and C(O)NR^(c)R^(c); and

each R^(c) is independently H or C₁₋₆ alkyl;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents.

In some embodiments:

R¹ is H or C₁₋₆ alkyl;

R² is OR¹³, C₆₋₁₀ aryl, or 5-10 membered heteroaryl; wherein said C₆₋₁₀aryl or 5-10 membered heteroaryl of R² are each optionally substitutedwith 1, 2, 3, 4, or 5 independently selected R^(j) substituents;

each R^(j) is independently selected from halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, NHOR^(k), OR^(k), C(O)R^(k),C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k),NR^(k)R^(k), NR^(k)C(O)R^(k), S(O)₂R^(k), NR^(k)S(O)₂R^(k), andS(O)₂NR^(k)R^(k);

R^(3a) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-GA alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(3a) are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(b)substituents;

R^(4a) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-; wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(4a) are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(b)substituents;

R³ is H or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is H, halo, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R^(5a) is H or C₁₋₆ alkyl;

R⁶ is H, halo, CN, C₁₋₆ alkyl, or C₁₋₆ haloalkyl; and

R⁷ is H, halo, CN, C₁₋₆ alkyl, or C₁₋₆ haloalkyl.

In some embodiments:

R¹ is C₁₋₆ alkyl;

R² is C₁₋₆ alkoxy, phenyl, or monocyclic 5-6 membered heteroaryl;wherein said C₆₋₁₀ aryl or monocyclic 5-6 membered heteroaryl of R² areeach optionally substituted with 1, 2, or 3 independently selected R^(j)substituents;

each R^(j) is independently selected from halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, NHOR^(k), OR^(k), C(O)R^(k),C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k),NR^(k)R^(k), NR^(k)C(O)R^(k), S(O)₂R^(k), NR^(k)S(O)₂R^(k), andS(O)₂NR^(k)R^(k);

each R^(k) is independently selected from H, C₁₋₄ alkyl, and C₁₋₄haloalkyl;

R^(3a) is H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl, and (4-6 memberedheterocycloalkyl)-C₁₋₄ alkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl, and (4-6 membered heterocycloalkyl)-C₁₋₄ alkyl of R^(3a) are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(b)substituents;

each R^(b) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, OH, NH₂, NHOR^(c), OR^(c), C(O)R^(c), C(O)NR^(c)R^(c),C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c) C(O)OR^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),S(O)₂12C and S(O)₂NR^(c) R^(c);

R^(4a) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl-C₁₋₄ alkyl-, and (5-6 membered heteroaryl)-C₁₋₄ alkyl-; whereinsaid C₁₋₆ alkyl, C₁₋₆ alkynyl, C3_7 cycloalkyl, phenyl-C₁₋₄ alkyl-, and(5-6 membered heteroaryl)-C₁₋₄ alkyl- of R^(4a) are each optionallysubstituted by 1, 2, 3, or 4 independently selected R^(b) substituents;

R³ is H or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R^(5a) is H or C₁₋₆ alkyl;

R⁵ is H, halo, or C₁₋₆ alkyl;

R⁶ is halo, CN, or C₁₋₆ alkyl; and

each R^(c) is independently H or C₁₋₆ alkyl;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents.

In some embodiments:

R¹ is C₁₋₆ alkyl;

R² is C₁₋₆ alkoxy or phenyl, wherein said phenyl of R² is optionallysubstituted with 1, 2, or 3 independently selected R substituents;

each R^(j) is independently selected from halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, anddi(C₁₋₄alkyl)amino;

R^(3a) is H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl, and (4-6 memberedheterocycloalkyl)-C₁₋₄ alkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl, and (4-6 membered heterocycloalkyl)-C₁₋₄ alkyl of R^(3a) are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(b)substituents;

R^(4a) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl-C₁₋₄ alkyl-, and (5-6 membered heteroaryl)-C₁₋₄ alkyl-; whereinsaid C₁₋₆ alkyl and (5-6 membered heteroaryl)-C₁₋₄ alkyl- of R^(4a) areeach optionally substituted by 1, 2, 3, or 4 independently selected Rbsubstituents;

R³ is H or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R^(5a) is H or C₁₋₆ alkyl;

R⁵ is H, halo, or C₁₋₆ alkyl;

R⁶ is halo, CN, or C₁₋₆ alkyl;

each R^(b) is independently selected from C₁₋₄ alkyl, OH, OR^(c), CN,and NR^(c)R^(c), and C(O)NR^(c) R^(c); and

each R^(c) is independently H or C₁₋₆ alkyl;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents.

In some embodiments:

R¹ is C₁₋₆ alkyl;

R² is C₁₋₆ alkoxy or phenyl, wherein said phenyl of R² is optionallysubstituted with 1, 2, or 3 independently selected R substituents;

each R^(j) is independently halo;

R^(3a) is H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl, and (4-6 memberedheterocycloalkyl)-C₁₋₄ alkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl, and (4-6 membered heterocycloalkyl)-C₁₋₄ alkyl of R^(3a) are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(b)substituents;

R^(4a) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl-C₁₋₄ alkyl-, and (5-6 membered heteroaryl)-C₁₋₄ alkyl-; whereinsaid C₁₋₆ alkyl and (5-6 membered heteroaryl)-C₁₋₄ alkyl- of R^(4a) areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(b) substituents;

R³ is H or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R^(5a) is H or C₁₋₆ alkyl;

R⁵ is H, halo, or C₁₋₆ alkyl;

R⁶ is halo, CN, or C₁₋₆ alkyl;

each R^(b) is independently selected from C₁₋₄ alkyl, OH, OR^(c), CN,and NR^(c)R^(c), and C(O)NR^(c) R^(c); and

each R^(c) is independently H or C₁₋₆ alkyl;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents.

In some embodiments:

R¹ is methyl;

R² is ethoxy, phenyl, or 3-fluorophenyl;

each R^(j) is independently halo;

R^(3a) is H, methyl, isopropyl, isobutyl, —CH₂C≡CCH₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, —CH₂CN, —CH₂CH₂NH₂, —CH₂C(O)NH₂, benzyl, cyclobutyl,—CH₂-(1-methyl-1H-pyrazol-3-yl), or —CH₂CH₂— (morpholin-4-yl);

R³ is H or methyl;

R^(4a) is H, methyl, ethyl, isopropyl, isobutyl, —CH₂C≡CCH₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, —CH₂CN, —CH₂CH₂NH₂, cyclobutyl, benzyl, —CH₂C(O)NH₂,—CH₂-(1-methyl-1H-pyrazol-3-yl), or —CH₂C(O)-(morpholin-4-yl);

R⁵ is H, bromo, or methyl; and

R⁶ is chloro, CN, or methyl.

In some embodiments, the compound is a compound of Formula X, XI, orXII:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is C₁₋₆ alkyl;

R² is C₁₋₆ alkoxy, phenyl, monocyclic 5-6 membered heterocycloalkyl,monocyclic 5-6 membered heteroaryl; wherein said C₆₋₁₀ aryl, monocyclic5-6 membered heterocycloalkyl, and monocyclic 5-6 membered heteroaryl ofR² are each optionally substituted with 1, 2, or 3 independentlyselected IV substituents;

each R^(j) is independently selected from halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, NHOR^(k), OR^(k), C(O)R^(k),C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k),NR^(k)R^(k), NR^(k)C(O)R^(k), S(O)₂R^(k), NR^(k)S(O)₂R^(k), andS(O)₂NR^(k)R^(k);

each R^(k) is independently selected from H, C₁₋₄ alkyl, and C₁₋₄haloalkyl;

R³ is H or C¹⁻⁶ alkyl;

R^(3a) is H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl, and (4-6 memberedheterocycloalkyl)-C₁₋₄ alkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl, and (4-6 membered heterocycloalkyl)-C₁₋₄ alkyl of R^(3a) are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(b)substituents;

each R^(b) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, OH, NH₂, NHOR^(c), OR^(c), C(O)R^(c), C(O)NR^(c)R^(c),C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), NHR^(c), NR^(c)R^(c),NR^(c)C(O)R^(c), NR^(c)(O)OR^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c);

R^(4a) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl-C₁₋₄ alkyl-, and (5-6 membered heteroaryl)-C₁₋₄ alkyl-; whereinsaid C₁₋₆ alkyl, C₁₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl-C₁₋₄ alkyl-, and(5-6 membered heteroaryl)-C₁₋₄ alkyl- of R^(4a) are each optionallysubstituted by 1, 2, 3, or 4 independently selected R^(b) substituents;

R³ is H or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R^(5a) is H or C₁₋₆ alkyl;

R⁵ is H, halo, or C₁₋₆ alkyl;

R⁶ is halo, CN, or C₁₋₆ alkyl;

R⁷, R⁸, R⁹ are each H; and

each R^(c) is independently H or C₁₋₆ alkyl;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents.

In some embodiments, the compound is a compound of Formula X, XI, orXII:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is C₁₋₆ alkyl;

R² is C₁₋₆ alkoxy, phenyl, 5-6 membered monocyclic heterocycloalkyl, ormonocyclic 5-6 membered heteroaryl; wherein said C₆₋₁₀ aryl ormonocyclic 5-6 membered heteroaryl of R² are each optionally substitutedwith 1, 2, or 3 independently selected R^(j) substituents;

each R^(j) is independently selected from halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, NHOR^(k), OR^(k), C(O)R^(k),C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k),NR^(k)R^(k), NR^(k)C(O)R^(k), S(O)₂R^(k), NR^(k)S(O)₂R^(k), andS(O)₂NR^(k)R^(k);

each R^(k) is independently selected from H, C₁₋₄ alkyl, and C₁₋₄haloalkyl;

R³ is H or C¹⁻⁶ alkyl;

R^(3a) is H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl, and (4-6 memberedheterocycloalkyl)-C₁₋₄ alkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl, and (4-6 membered heterocycloalkyl)-C₁₋₄ alkyl of R^(3a) are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(b)substituents;

each R^(b) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, OH, NH₂, NHOR^(c), OR^(c), C(O)R^(c), C(O)NR^(c)R^(c),C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c) C(O)OR^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c);

R^(4a) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl-C₁₋₄ alkyl-, and (5-6 membered heteroaryl)-C₁₋₄ alkyl-; whereinsaid C₁₋₆ alkyl, C₁₋₆ alkynyl, C3_7 cycloalkyl, phenyl-C₁₋₄ alkyl-, and(5-6 membered heteroaryl)-C₁₋₄ alkyl- of R⁴a are each optionallysubstituted by 1, 2, 3, or 4 independently selected Rh substituents;

R³ is H or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R^(5a) is H or C₁₋₆ alkyl;

R⁵ is H, halo, or C₁₋₆ alkyl;

R⁶ is halo, CN, or C₁₋₆ alkyl;

R⁷, R⁸, R⁹ are each H; and

each R^(c) is independently H or C₁₋₆ alkyl;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents.

In some embodiments, the compound is a compound of Formula X, XI, orXII:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is C₁₋₆ alkyl;

R² is C₁₋₆ alkoxy, phenyl, or monocyclic 5-6 membered heteroaryl;wherein said C₆₋₁₀ aryl or monocyclic 5-6 membered heteroaryl of R² areeach optionally substituted with 1, 2, or 3 independently selected R^(j)substituents;

each R^(j) is independently selected from halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, NHOR^(k), OR^(k), C(O)R^(k),C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k),NR^(k)R^(k), NR^(k)C(O)R^(k), S(O)₂R^(k), NR^(k)S(O)₂R^(k), andS(O)₂NR^(k)R^(k);

each R^(k) is independently selected from H, C₁₋₄ alkyl, and C₁₋₄haloalkyl;

R³ is H or C¹⁻⁶ alkyl;

R^(3a) is H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl, and (4-6 memberedheterocycloalkyl)-C₁₋₄ alkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl, and (4-6 membered heterocycloalkyl)-C₁₋₄ alkyl of R^(3a) are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(b)substituents;

each R^(b) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, OH, NH₂, NHOR^(c), OR^(c), C(O)R^(c), C(O)NR^(c)R^(c),C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), NHR^(c), NR^(c)R^(c),NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c);

R^(4a) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl-C₁₋₄ alkyl-, and (5-6 membered heteroaryl)-C₁₋₄ alkyl-; whereinsaid C₁₋₆ alkyl, C₁₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl-C₁₋₄ alkyl-, and(5-6 membered heteroaryl)-C₁₋₄ alkyl- of R^(4a) are each optionallysubstituted by 1, 2, 3, or 4 independently selected R^(b) substituents;

R³ is H or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R^(5a) is H or C₁₋₆ alkyl;

R⁵ is H, halo, or C₁₋₆ alkyl;

R⁶ is halo, CN, or C₁₋₆ alkyl;

R⁷, R⁸, R⁹ are each H; and

each R^(c) is independently H or C₁₋₆ alkyl;

or any two W substituents together with the nitrogen atom to which theyare attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 independently selected R^(h)substituents.

In some embodiments, the compound is a compound of Formula X, XI, orXII:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is C₁₋₆ alkyl;

R² is C₁₋₆ alkoxy or phenyl, wherein said phenyl of R² is optionallysubstituted with 1, 2, or 3 independently selected R^(j) substituents;

each R^(j) is independently selected from halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, anddi(C₁₋₄alkyl)amino;

R³ is H or C₁₋₆ alkyl;

R^(3a) is H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl, and (4-6 memberedheterocycloalkyl)-C₁₋₄ alkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl, and (4-6 membered heterocycloalkyl)-C₁₋₄ alkyl of R^(3a) are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(b)substituents;

R^(4a) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl-C₁₋₄ alkyl-, and (5-6 membered heteroaryl)-C₁₋₄ alkyl-; whereinsaid C₁₋₆ alkyl and (5-6 membered heteroaryl)-C₁₋₄ alkyl- of R^(4a) areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(b) substituents;

R³ is H or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R^(5a) is H or C₁₋₆ alkyl;

R⁵ is H, halo, or C₁₋₆ alkyl;

R⁶ is halo, CN, or C₁₋₆ alkyl;

R⁷, R⁸, R⁹ are each H;

each R^(b) is independently selected from C₁₋₄ alkyl, OH, OR^(c), CN,and NR^(c)R^(c), and C(O)NR^(c)R^(c); and

each R^(c) is independently H or C₁₋₆ alkyl;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents.

In some embodiments, the compound is a compound of Formula X, XI, orXII:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is C₁₋₆ alkyl;

R² is C₁₋₆ alkoxy or phenyl, wherein said phenyl of R² is optionallysubstituted with 1, 2, or 3 independently selected IV substituents;

each R^(j) is independently halo;

R³ is H or C₁₋₆ alkyl;

R^(3a) is H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl, and (4-6 memberedheterocycloalkyl)-C₁₋₄ alkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl, and (4-6 membered heterocycloalkyl)-C₁₋₄ alkyl of R^(3a) are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(b)substituents;

R^(4a) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl-C₁₋₄ alkyl-, and (5-6 membered heteroaryl)-C₁₋₄ alkyl-; whereinsaid C₁₋₆ alkyl and (5-6 membered heteroaryl)-C₁₋₄ alkyl- of R^(4a) areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(b) substituents;

R³ is H or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R^(5a) is H or C₁₋₆ alkyl;

R⁵ is H, halo, or C₁₋₆ alkyl;

R⁶ is halo, CN, or C₁₋₆ alkyl;

R⁷, R⁸, R⁹ are each H;

each R^(b) is independently selected from C₁₋₄ alkyl, OH, OR^(c), CN,and NR^(c)R^(c), and C(O)NR^(c)R^(c); and

each R^(c) is independently H or C₁₋₆ alkyl;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents.

In some embodiments, the compound is a compound of Formula X, XI, orXII:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is methyl;

R² is ethoxy, phenyl, 3-fluorophenyl, or2-methyl-1,1-dioxidothiomorpholino; each R^(j) is independently halo;

R³ is H or methyl;

R^(3a) is H, methyl, isopropyl, isobutyl, —CH₂C≡CCH₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, —CH₂CN, —CH₂CH₂NH₂, —CH₂C(O)NH₂, benzyl, cyclobutyl,—CH₂-(1-methyl-1H-pyrazol-3-yl), or —CH₂CH₂-(morpholin-4-yl);

R^(4a) is H, methyl, ethyl, isopropyl, isobutyl, —CH₂C≡CH₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, —CH₂CN, —CH₂CH₂NH₂, cyclobutyl, benzyl, —CH₂C(O)NH₂,—CH₂-(1-methyl-1H-pyrazol-3-yl), or —CH₂C(O)-(morpholin-4-yl);

R⁵ is H, bromo, or methyl;

R⁶ is chloro, CN, or methyl; and

R⁷, R⁸, and R⁹ are each H.

In some embodiments, the compound is a compound of Formula X, XI, orXII:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is methyl;

R² is ethoxy, phenyl, or 3-fluorophenyl;

each R^(j) is independently halo;

R³ is H or methyl;

R^(3a) is H, methyl, isopropyl, isobutyl, —CH₂C≡CCH₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, —CH₂CN, —CH₂CH₂NH₂, —CH₂C(O)NH₂, benzyl, cyclobutyl,—CH₂-(1-methyl-1H-pyrazol-3-yl), or —CH₂CH₂-(morpholin-4-yl);

R^(4a) is H, methyl, ethyl, isopropyl, isobutyl, —CH₂C≡CCH₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, —CH₂CN, —CH₂CH₂NH₂, cyclobutyl, benzyl, —CH₂C(O)NH₂,—CH₂-(1-methyl-1H-pyrazol-3-yl), or —CH₂C(O)-(morpholin-4-yl);

R⁵ is H, bromo, or methyl;

R⁶ is chloro, CN, or methyl; and

R⁷, R⁸, and R⁹ are each H.

In some embodiments, the compound is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (IV):

or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound is a compound of Formula (V):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (VI):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (VII):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (VIII):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (IX):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (X):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (X), or apharmaceutically acceptable salt thereof, wherein R^(4a) is H, C₁₋₆alkyl, C₂₋₆ alkynyl, benzyl, cyanomethyl, 2-methoxyethyl,2-hydroxyethyl, cyclobutyl, cyclopentyl, 2-amino-2-oxoethyl,N,N-dimethyl-2-amino-2-oxoethyl, (1-methyl-1H-pyrazol-3-yl)methyl,2-morpholinoethyl, 2-morpholino-2-oxoethyl or 2-aminoethyl.

In some embodiments, the compound is a compound of Formula (X), or apharmaceutically acceptable salt thereof, wherein R² is ethoxy or phenyloptionally substituted with halo.

In some embodiments, the compound is a compound of Formula (X), or apharmaceutically acceptable salt thereof, wherein R¹ is methyl.

In some embodiments, the compound is a compound of Formula (X), or apharmaceutically acceptable salt thereof, wherein R⁵ is H, Br or methyl.

In some embodiments, the compound is a compound of Formula (X), or apharmaceutically acceptable salt thereof, wherein R⁶ is methyl, CN orCl.

In some embodiments, the compound is a compound of Formula (X), or apharmaceutically acceptable salt thereof, wherein R⁷, R⁸ and R⁹ are eachH.

In some embodiments, the compound is a compound of Formula (XI):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (XI), or apharmaceutically acceptable salt thereof, wherein R^(4a) is H, C₁₋₆alkyl, C₂₋₆ alkynyl, benzyl, cyanomethyl, 2-methoxyethyl,2-hydroxyethyl, cyclobutyl, cyclopentyl, 2-amino-2-oxoethyl,N,N-dimethyl-2-amino-2-oxoethyl, (1-methyl-1H-pyrazol-3-yl)methyl,2-morpholinoethyl, 2-morpholino-2-oxoethyl or 2-aminoethyl.

In some embodiments, the compound is a compound of Formula (XI), or apharmaceutically acceptable salt thereof, wherein R² is ethoxy,1,1-dioxidothiomorpholino optionally substituted with 1 or 2independently selected C₁₋₄ alkyl substituents, or phenyl optionallysubstituted with halo.

In some embodiments, the compound is a compound of Formula (XI), or apharmaceutically acceptable salt thereof, wherein R² is ethoxy or phenyloptionally substituted with halo.

In some embodiments, the compound is a compound of Formula (XI), or apharmaceutically acceptable salt thereof, wherein R¹ is methyl.

In some embodiments, the compound is a compound of Formula (XI), or apharmaceutically acceptable salt thereof, wherein R⁵ is H, Br or methyl.

In some embodiments, the compound is a compound of Formula (XI), or apharmaceutically acceptable salt thereof, wherein R⁶ is methyl, CN orCl.

In some embodiments, the compound is a compound of Formula (XI), or apharmaceutically acceptable salt thereof, wherein R⁷ is H,piperidin-1-yl, or pyridin-3-yl optionally substituted by C₁₋₄ alkyl orC₁₋₄ alkoxy, wherein the C₁₋₄ alkyl group is substituted by OH.

In some embodiments, the compound is a compound of Formula (XI), or apharmaceutically acceptable salt thereof, wherein R⁷, R⁸ and R⁹ are eachH.

In some embodiments, the compound is a compound of Formula (XII):

or a pharmaceutically acceptable salt thereof

In some embodiments, the compound is2-amino-N-((S)-1-(8-chloro-5-((R)-2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is2-amino-N—((S)-1-(8-chloro-5-((S)-2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide,or a pharmaceutically acceptable salt thereof.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. The substituents are independently selected, andsubstitution may be at any chemically accessible position. As usedherein, the term “substituted” means that a hydrogen atom is removed andreplaced by a substituent. A single divalent substituent, e.g., oxo, canreplace two hydrogen atoms. It is to be understood that substitution ata given atom is limited by valency.

Throughout the definitions, the term “C.” indicates a range whichincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₄, C₁₋₆, and the like.

As used herein, the term “C_(n-m)alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. Examplesof alkyl moieties include, but are not limited to, chemical groups suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl,sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl,n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, thealkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms,from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylene”, employed alone or incombination with other terms, refers to a divalent alkyl linking grouphaving n to m carbons. Examples of alkylene groups include, but are notlimited to, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,1,-diyl,propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl,butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like. In someembodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to6, 1 to 4, or 1 to 2 carbon atoms.

As used herein, the term “C-_m alkoxy”, employed alone or in combinationwith other terms, refers to a group of formula -O-alkyl, wherein thealkyl group has n to m carbons. Example alkoxy groups include, but arenot limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m)alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms. Examples of alkylamino groups include, but are not limited to,N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino andN-isopropylamino), N-butylamino (e.g., N-(n-butyl)amino andN-(tert-butyl)amino), and the like.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to an aromatic hydrocarbon group, which may bemonocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term“C_(n-m)aryl” refers to an aryl group having from n to m ring carbonatoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl,phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, arylgroups have from 6 to 10 carbon atoms. In some embodiments, the arylgroup is phenyl or naphthyl.

As used herein, the term “di(C_(n-m)-alkyl)amino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, ahalo is F, Cl, or Br.

As used herein, “C_(n-m)haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. An example haloalkoxy group isOCF₃. In some embodiments, the haloalkoxy group is fluorinated only. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m)haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and/or alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groupsand spirocycles. Ring-forming carbon atoms of a cycloalkyl group can beoptionally substituted by oxo or sulfido (e.g., C(O) or C(S)). Alsoincluded in the definition of cycloalkyl are moieties that have one ormore aromatic rings fused (i.e., having a bond in common with) to thecycloalkyl ring, for example, benzo or thienyl derivatives ofcyclopentane, cyclohexane, and the like. A cycloalkyl group containing afused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Cycloalkylgroups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C₃₋₁₀).In some embodiments, the cycloalkyl is a C₃₋₁₀ monocyclic or bicycliccyclocalkyl. In some embodiments, the cycloalkyl is a C₃₋₇ monocycliccyclocalkyl. Example cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, andthe like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen, and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3, or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having1, 2, 3 or 4 heteroatom ring members independently selected fromnitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with aring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ringatoms are independently selected from N, O, and S. Exemplaryfive-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl,thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroarylring is a heteroaryl with a ring having six ring atoms wherein one ormore (e.g., 1, 2, or 3) ring atoms are independently selected from N, O,and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl,pyrimidinyl, triazinyl and pyridazinyl.

As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic orpolycyclic heterocycles having one or more ring-forming heteroatomsselected from O, N, or S. Included in heterocycloalkyl are monocyclic4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl groups.Heterocycloalkyl groups can also include spirocycles. Exampleheterocycloalkyl groups include pyrrolidin-2-one,1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl,morpholino, thiomorpholino, 1,1-dioxidothiomorpholin-4-yl,1,2,3,6-tetrahydropyridin-4-yl, 1,1-dioxido-1,4-thiazepan-4-yl,1,1-dioxido-1,2,5-thiadiazepan-5-yl, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl,isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbonatoms and heteroatoms of a heterocycloalkyl group can be optionallysubstituted by oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)₂, etc.).The heterocycloalkyl group can be attached through a ring-forming carbonatom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the cycloalkyl ring, for example, benzo or thienyl derivativesof piperidine, morpholine, azepine, etc. A heterocycloalkyl groupcontaining a fused aromatic ring can be attached through anyring-forming atom including a ring-forming atom of the fused aromaticring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6membered heterocycloalkyl having 1 or 2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur and having one or moreoxidized ring members. In some embodiments, the heterocycloalkyl is amonocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or4 heteroatoms independently selected from nitrogen, oxygen, or sulfurand having one or more oxidized ring members. In some embodiments, theheterocycloalkyl is a monocyclic or bicyclic 4-10 memberedheterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur and having one or more ring membersselected from C(O), S(O), C(S), S(O)₂, and S(NH)(O). In someembodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur and having one or more ringmembers selected from S(O)₂ and S(NH)(O).

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas a pyridin-3-yl ringis attached at the 3-position.

As used herein, the term “oxo” refers to an oxygen atom as a divalentsubstituent, forming a carbonyl group when attached to a carbon (e.g.,C=O), or attached to a heteroatom forming a sulfoxide or sulfone group.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms. In someembodiments, the compound has the (R)-configuration. In someembodiments, the compound has the (S)-configuration.

Formulas (I)-(XII) herein include stereoisomers of the compounds. Insome embodiments, the carbon atom to which R¹ is attached is in the(R)-configuration. In some embodiments, the carbon atom to which R¹ isattached is in the (S)-configuration.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolutionof racemic mixtures can also be carried out by elution on a columnpacked with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds provided herein also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam—lactim pairs, enamine—imine pairs, and annular forms herea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.hydrates and solvates) or can be isolated.

In some embodiments, preparation of compounds can involve the additionof acids or bases to affect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

Example acids can be inorganic or organic acids and include, but are notlimited to, strong and weak acids. Some example acids includehydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,p-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid,benzenesulfonic acid, trifluoroacetic acid, and nitric acid. Some weakacids include, but are not limited to acetic acid, propionic acid,butanoic acid, benzoic acid, tartaric acid, pentanoic acid, hexanoicacid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid.

Example bases include lithium hydroxide, sodium hydroxide, potassiumhydroxide, lithium carbonate, sodium carbonate, potassium carbonate, andsodium bicarbonate. Some example strong bases include, but are notlimited to, hydroxide, alkoxides, metal amides, metal hydrides, metaldialkylamides and arylamines, wherein; alkoxides include lithium, sodiumand potassium salts of methyl, ethyl and t-butyl oxides; metal amidesinclude sodium amide, potassium amide and lithium amide; metal hydridesinclude sodium hydride, potassium hydride and lithium hydride; and metaldialkylamides include lithium, sodium, and potassium salts of methyl,ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, trimethylsilyl andcyclohexyl substituted amides.

In some embodiments, the compounds provided herein, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds providedherein. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds provided herein, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. One ormore constituent atoms of the compounds of the invention can be replacedor substituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present application also includes pharmaceutically acceptable saltsof the compounds described herein. The present invention also includespharmaceutically acceptable salts of the compounds described herein. Asused herein, “pharmaceutically acceptable salts” refers to derivativesof the disclosed compounds wherein the parent compound is modified byconverting an existing acid or base moiety to its salt form. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts of the present inventioninclude the conventional non-toxic salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol, or butanol) or acetonitrile (ACN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporatedherein by reference in its entirety.

Synthesis

As will be appreciated, the compounds provided herein, including saltsand stereoisomers thereof, can be prepared using known organic synthesistechniques and can be synthesized according to any of numerous possiblesynthetic routes.

Compounds of Formula I can be prepared from amines 1-1 as shown inScheme 1. Amine 1-1 can be coupled with an optionally protected (e.g.,P=Boc) carboxylic acid such as 1-2 by various methods (e.g., treatmentwith a coupling reagent, such asN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate in the presence of base, such asdiisopropylethylamine). After coupling, optionally chosen protectinggroups can be removed under conditions suitable for their removal, thatare also compatible with the functionality present in the resultingcompounds of Formula I.

Amines 1-1 can be prepared from ketones 2-1 by various methods, asillustrated in Scheme 2. For example, one method (A) involves imineformation with a source of ammonia (e.g. solution of ammonia in analcohol, or an ammonium salt such as ammonium acetate), which may befacilitated by the introduction of a Lewis acid (e.g. titanium(IV)ethoxide or titanium tetraisopropoxide). The imine can be reduced usinga reducing agent (e.g. NaBH₄ or NaCNBH₃), to furnish amines 1-1.Alternatively, the method of Ellman (B), can be used to furnish amine1-1 in enantiomerically enriched form. This would be performed, forexample, by condensation of ketones 2-1 with a tert-butanesulfinamide(chiral, if desired) in the presence of Lewis acid (e.g., titaniumtetraethoxide), followed by reduction of the tert-butanesulfinylketimine (e.g. using L-Selectride), and removal of the tert-butylsulfinyl group with acid (e.g., 4 N HCl in dioxane). As an alternativeto reductive amination, a sequence of transformations (C) can be used tofurnish amine 1-1, which include reduction of the ketone to the alcohol(e.g. using NaBH₄), conversion of the resulting alcohol to a leavinggroup (e.g., reacting with MsCl in the presence of base, such astriethylamine), displacement of the leaving group with sodium azide,followed by reduction of the azide to an amine (e.g., via hydrogenationor Staudinger reduction).

As shown in Scheme 3, ketones 2-1 can be prepared from esters 3-1 viasequential hydrolysis (e.g. treatment with a hydroxide base, such asNaOH), Weinreb amide formation (e.g. by coupling the acid withN,O-dimethylhydroxylamine using a coupling agent such as EDCI and HOBtin the presence of a tertiary amine base, such as triethylamine ordiisopropylethylamine), and treatment of the Weinreb amide with aGrignard reagent, R¹-MgX, to afford ketone 2-1.

Compounds of Formula I wherein W═CH, X¹═C, X²═C, X³═N or NR^(3a), X⁴═Nor NR^(4a), X⁵═CR⁵ can be prepared as shown in Scheme 4.Nitro-containing starting materials 4-1 can be converted to thecorresponding triflate 4-2 by several methods (e.g., by treatment withtrifluoromethanesulfonic anhydride and a base, such as triethylamine).The substituent R² can be introduced by a coupling of 4-2 with R²-M,where M is a boronic acid, boronic ester, or an appropriatelysubstituted metal such as Sn(Bu)₄ or Zn, under standard Suzukiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., abicarbonate or carbonate base, or CsF)) or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to givederivative 4-3. The nitro group of intermediate 4-3 can be converted tothe primary amine by reduction (e.g. hydrogenation over a Pt or Pdcatalyst, Fe/HCl, or LiAlH₄). Intermediate 4-4 can then be converted tothe indazole via diazotization of the amine and cyclization employing analkyl nitrite (e.g., amyl nitrite) in warm AcOH. If desired, the halogenpresent in 4-5 can serve as a handle for installation of substituent R⁶,via coupling with R⁶-M, where M is a boronic acid, boronic ester, or anappropriately substituted metal such as Sn(Bu)4 or Zn, under standardSuzuki conditions (e.g., in the presence of a palladium catalyst, suchas tetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., abicarbonate or carbonate base, or CsF)) or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to givederivative 4-6. The indazole nitrogens of 4-6 can be alkylated either bytreatment with a base and an electrophile, such as an alkyl halide (e.g.K₂CO₃ and MeI), or via Mitsunobu conditions (PPh₃, DEAD) employing asuitable alcohol, to give 4-7 as a mixture of Ni and N2 substitutedindazoles. The ketone in 4-7 can be converted to an amine by variousmethods as shown in Scheme 2 to furnish amine 4-8. Amine 4-8 can becoupled with an optionally protected carboxylic acid such as 1-2 (fromScheme 1) by various methods as shown in Scheme 1. After coupling, anychosen protecting groups can be removed under conditions suitable fortheir removal, that are also compatible with the functionality presentin the resulting compounds of the Formula I. It will be recognized byone skilled in the art that the order of steps in Scheme 4 can bechanged in consideration of compatibility of functional groups presentin the intermediates.

Alkoxy derivatives of the compounds of Formula I, where R²═OR¹³ can beprepared as shown in Scheme 5. Alkylation of the hydroxyl group in 4-1employing a base and an electrophile such as an alkyl halide (e.g. K₂CO₃and MeI) provides alkoxy intermediates 5-1, which can be converted tocompounds of Formula I employing the synthetic methodologies describedin Schemes 1 and 2. It will be recognized by one skilled in the art thatthe order of steps in Scheme 5 can be changed in consideration of thecompatibility of functional groups present in the intermediates.

Alternatively, compounds of Formula I wherein W═CH, X¹═C, X²═C, X³═N orNR^(3a), X⁴═N or NR^(4a), X⁵=CR⁵ can be synthesized by the syntheticroute outlined in Scheme 6. The ketone 4-6 can be converted to an amine6-1 by various methods as outlined in Scheme 2. Amine 6-1 can be coupledwith an optionally protected carboxylic acid such as 1-2 (from Scheme 1)by various methods (e.g., treatment with a coupling reagent such asN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate in the presence of base, such asdiisopropylethylamine). The indazole nitrogens of 6-2 can be alkylatedeither by treatment with a base and an electrophile such as an alkylhalide (e.g. K₂CO₃ and MeI), or via Mitsunobu conditions (PPh₃, DEAD)employing a suitable alcohol, to give 6-3 as a mixture of N1 and N2substituted indazoles. Any chosen protecting groups can then be removedunder conditions suitable for their removal that are also compatiblewith the functionality present in the resulting compounds of theinvention. It will be recognized by one skilled in the art that theorder of steps in Scheme 6 can be changed in consideration ofcompatibility of functional groups present in the intermediates.

Compounds of Formula I wherein X¹═C, X²═C, X³═N or NR^(3a), X⁴═N orNR^(4a), X⁵═CR⁵ can also be prepared by the synthetic route described inScheme 7. Halogenation of heterocycle 4-6 with reagents such as I₂, Br₂,N-bromosuccinimide, or N-iodosuccinimide can furnish intermediate 7-1,which can serve as a substrate for introduction of substituent R⁵, viacoupling with R⁵-M, where M is a boronic acid, boronic ester, or anappropriately substituted metal such as Sn(Bu)₄ or Zn, under standardSuzuki conditions (e.g., in the presence of a palladium catalyst, suchas tetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., abicarbonate or carbonate base, or CsF)) or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to yieldintermediate 7-2. The ketone 7-2 can be converted to an amine 7-3 byvarious methods as illustrated in Scheme 2. Amine 7-3 can be coupledwith an optionally protected carboxylic acid such as 1-2 (from Scheme 1)by various methods (e.g., treatment with a coupling reagent such asN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate in the presence of base, such asdiisopropylethylamine) to provide 7-4. The indazole nitrogens in 7-4 canoptionally be alkylated either by treatment with a base and anelectrophile, such as an alkyl halide (e.g. K₂CO₃ and MeI), or viaMitsunobu conditions (PPh₃, DEAD) employing a suitable alcohol, to givea mixture of N1 and N2 substituted indazoles. Any chosen protectinggroups can then be removed under conditions known by ones skilled in theart, that are also compatible with the functionality present in theresulting compounds of the invention. It will be recognized by oneskilled in the art that the order of steps in Scheme 7 can be changed inconsideration of compatibility of functional groups present in theintermediates.

Compounds of Formula I, wherein W═CH, Z¹═C, Z²═N, X³═N, X⁴═CR⁴, X⁵═CR⁵can be synthesized as shown in Scheme 8. Accordingly, a carboxylic acidof formula 8-1 can be reacted to form an ester by various methods, suchas conversion of the carboxylic acid to the acid chloride by reactionwith COCl₂ and DMF in a suitable solvent such as DCM, followed byreaction of the acid chloride with a suitable alcohol. The substituentR² can subsequently be introduced by coupling with R²-M, where M is aboronic acid, boronic ester, or an appropriately substituted metal suchas Sn(Bu)₄ or Zn, under standard Suzuki conditions (e.g., in thepresence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., abicarbonate or carbonate base, or CsF)) or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to givederivative 8-2. Compound 8-2 can then be aminated with an electrophilicamination reagent (e.g., 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene)to form a N-amino derivative of formula 8-3. Compound 8-3 could then bereacted with a suitable acetylene 8-4 to form a heterocycle of formula8-5. Compound 8-5 could then be selectively decarboxylated (e.g., aciddeprotection of R=t-buyl with trifluoroacetic acid followed bydecarboxylation) to form a heterocycle of formula 8-6, which can behalogenated (e.g., X═Cl, Br, I using agents such as anN-halosuccinimide) to give compounds of formula 8-7. If desired, thehalogen present in 8-7 can serve as a handle for installation ofsubstituent R⁵, via coupling with R⁵-M, where M is a boronic acid,boronic ester, or an appropriately substituted metal such as Sn(Bu)₄ orZn, under standard Suzuki conditions (e.g., in the presence of apalladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., abicarbonate or carbonate base, or CsF)) or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to givederivative 8-8. Formation of ketone 8-9 from ester 8-8 can be achievedby several methods such as those described in Scheme 3. Intermediates ofthe formula 8-9 can be converted to compounds of Formula I viaconversion to an amine via methods outlined in Scheme 2, followed bycoupling and deprotection as outlined in Scheme 1. It will be recognizedby one skilled in the art that the order of steps in Scheme 8 can bechanged in consideration of compatibility of functional groups presentin the intermediates.

Compounds of Formula I, wherein W═CH, X¹═C, X²═N, X³═CR³, X⁴═N, andX⁵═CR⁵, can be prepared as shown in Scheme 9. Halo-containing startingmaterials (9-1) can be esterified by various methods (e.g., conversionof the carboxylic acid to the acid chloride by reaction with COCl₂ andDMF in a suitable solvent such as DCM, followed by reaction of the acidchloride with a suitable alcohol, such as EtOH). The ester intermediatecan then be treated with an oxidizing reagent (e.g., a peroxide reagentsuch as the combination of H₂O₂/TFA) to form the heterocyclic N-oxide,and subsequently be converted to the nitrile derivative 9-2 (e.g., byheating with trimethylsilylcyanide and base). The substituent R² can beintroduced by a coupling of 9-2 with R²-M, where M is a boronic acid,boronic ester, or an appropriately substituted metal such as Sn(Bu)₄ orZn, under standard Suzuki conditions (e.g., in the presence of apalladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., abicarbonate or carbonate base, or CsF)) or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to givederivative 9-3. The nitrile of intermediate 9-3 can be converted to anaminomethyl group by reduction (e.g. using H₂ and a catalyst, such asRaney® Ni or Pd on carbon). Following reduction, the aminomethyl groupcan be acylated (e.g. by reacting with R³—CO-LG, wherein CO-LG is asuitable activated carbonyl group (e.g., an acid chloride (LG═Cl) oranhydride (LG═O—(CO)R), or carboxylic acid in combination with acoupling agent (e.g., BOP, HATU, or EDCl/HOBt) and a base (e.g.,diisopropylethylamine)). The acylated intermediate can be cyclized toform the bicyclic intermediate 9-4 under cyclo-dehydrating conditions(e.g. by heating in POCl₃ or by treatment with P₂O₅, SOCl₂ or withacid). Formation of ketone 9-5 from ester 9-4 can proceed as illustratedin Scheme 3. If desired, the halogen present in 9-5 (i.e., group X) canserve as a handle for installation of substituent R⁶, via coupling withR⁶-M, where M is a boronic acid, boronic ester, or an appropriatelysubstituted metal such as Sn(Bu)₄ or Zn, under standard Suzukiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., abicarbonate or carbonate base, or CsF)) or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to givederivative 9-6. If desired, treatment of 9-6 with a halogenating reagent(e.g. I₂, Br₂, N-chlorosuccinimide N-bromosuccinimide, orN-iodosuccinimide) can furnish intermediate 9-7 (wherein X═Cl, Br, I),which can be substituted with R⁵, via coupling with R⁵-M, where M is aboronic acid, boronic ester, or an appropriately substituted metal suchas Sn(Bu)₄ or Zn, under standard Suzuki conditions (e.g., in thepresence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., abicarbonate or carbonate base, or CsF)) or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to yieldintermediate ketone 9-8. Ketone 9-8 can be treated with one of theconditions of Scheme 2 to provide an amine that can be converted tocompounds of the invention 9-9 according to Scheme 1. It will berecognized by one skilled in the art that the order of steps in Scheme 9can be changed in consideration of compatibility of functional groupspresent in the intermediates.

Compounds of Formula I, wherein W═CH, X¹═C, X²═N, X³═CR³, X⁴═N, andX⁵═CR⁵, can also be prepared as shown in Scheme 9b. This changing of theorder of steps of Scheme 9 enables R² to be introduced at a later stagein the synthesis and can provide for introduction of R² with sensitivefunctional groups. Halo-containing starting materials 9-1 can beconverted to the Weinreb amide 9b-1 (e.g., by reaction with MeONHMe inthe presence of a suitable coupling reagent such as EDCI and in thepresence of HOBt and a suitable base, such as Hunig's base). The amideintermediate 9b-1 can then be treated with an oxidizing reagent (e.g., aperoxide reagent such as the combination of H₂O₂/TFA) to form theheterocyclic N-oxide, and subsequently be converted to the nitrilederivative 9b-1 (e.g., by heating with trimethylsilylcyanide and base).The nitrile of intermediate 9b-1 can be converted to an aminomethylgroup by reduction (e.g. Raney® Ni in formic acid). Following reduction,the aminomethyl group can be acylated (e.g. by reacting with R³—CO-LG,wherein CO-LG is a suitable activated carbonyl group (e.g., an acidchloride (LG═CO or anhydride (LG═O—(CO)R), or carboxylic acid incombination with a coupling agent (e.g., BOP, HATU, or EDCl/HOBt) and abase (e.g., diisopropylethylamine)). The acylated intermediate can becyclized to form the bicyclic intermediate 9b-2 under cyclo-dehydratingconditions (e.g. by heating in POCl₃ or by treatment with P₂O₅, SOCl₂ orwith acid). The Weinreb amide of intermediate 9b-2 can undergo reactionwith a Grignard reagent R¹MgX to afford ketone 9b-3. The substituent R²can be introduced by a coupling of 9b-3 with R²-M, where M is a boronicacid, boronic ester, or an appropriately substituted metal such asSn(Bu)₄ or Zn, under standard Suzuki conditions (e.g., in the presenceof a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., abicarbonate or carbonate base, or CsF)) or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to givederivative 9-5. Intermediates 9-5 can be transformed to furtherfunctionalized compounds of Formula I by the methods outlined in Scheme9.

Compounds of Formula I, wherein W═CH, X¹═C, X²═N, X³═CR³, X⁴═N, X⁵═CR⁵,and R²═NR¹⁰R¹¹ can be prepared by modification of Scheme 9 shown inScheme 9c. Intermediate 9-2 can be heated in the presence of an amine(R¹⁰R¹¹NH) and in the presence of a suitable base (e.g. cesium carbonateor Hunig's base) in a suitable solvent (e.g. acetonitrile) to provideintermediates 9c-1. The imidazole ring can be annealed to provideintermediate 9c-2, which can be elaborated to ketone 9c-3, which can befunctionalized to afford 9c-4, 9c-5 and 9c-6, and finally elaborated tocompounds of Formula I using methods previously outlined in Scheme 9.

As an alternative to early introduction of the amine as shown in Scheme9c, it is occasionally preferable to introduce it at a later stage asshown in Scheme 9d. Thus, compounds of Formula I, wherein W═CH, X¹═C,X²═N, X³═CR³, X⁴═N, X⁵═CR⁵, and R²═NR¹⁰R¹¹ can be prepared by heating(e.g., at temperatures ranging from 70 to 170° C.) the intermediate 9b-3with an amine (R¹⁰R¹¹NH) in the presence of a suitable base (e.g. cesiumcarbonate or Hunig's base) in a suitable solvent (e.g. acetonitrile) toprovide intermediate 9c-3. Intermediate ketone 9c-3 can be furtherfunctionalized and elaborated to compounds of Formula I using methodsalready described for Scheme 9 and Scheme 9c.

Amine-containing intermediates suitable for synthesis of compounds ofFormula I, wherein W═CH, X¹═C, X²═N, X³═CR³, X⁴═N, X⁵═CR⁵, andR²=NR¹⁰R¹¹ can be prepared as shown in Scheme 9e. The reaction ofWeinreb amide 9b-2 with an amine (R¹⁰R¹¹NH) in the presence of asuitable base (e.g. cesium carbonate or Hunig's base) in a suitablesolvent (e.g. acetonitrile) furnishes adduct 9e-1, which is veryflexible for further transformations. Intermediate Weinreb amide 9e-1can undergo reaction with Grignard reagents R¹MgX to afford ketones oftype 9e-2 that can be treated according to the methods of Scheme 2 toafford amines 9e-5 which, in turn, can be converted to compounds ofFormula I as outlined in Scheme 1. Alternatively, Weinreb amide 9e-1 canbe reduced by a suitable reducing agent (e.g. diisobutylaluminumhydride) to afford aldehyde 9e-3. Aldehyde 9e-3 can either be convertedto amine 9e-4 by one of the methods of Scheme 2, or converted to amine9e-5 by condensation with tert-butylsulfinamide (chiral, if desired) inthe presence of lewis acid (e.g. titanium isopropoxide), followed byreaction of the tert-butanesulfinyl aldimine with a Grignard reagentR¹MgX, and removal of the tert-butyl sulfinyl group with acid (e.g. 4NHCl in dioxane). Amines 9e-4 and 9e-5 serve as useful intermediates forfurther functionalization and elaboration to compounds of Formula Iaccording to methods outlined in Scheme 9. It will be recognized by oneskilled in the art that substituents at R⁵ and R⁶ can be introduced onmany of the intermediates at various stages in Scheme 9d and Scheme 9e,according to the compatibility of functional groups with the subsequentsteps to be performed.

Compounds of Formula I, wherein W═CH, X¹═C, X²═N, X³═CR³, X⁴═CR⁴ andX⁵═N, can be prepared as shown in Scheme 10. An amino heterocycle, suchas 10-1, can be halogenated according to a procedure as found in US2008-0019915, involving protection of the amino moiety with a suitableprotecting group (e.g., phthalimide), formation of the N-oxide using asuitable oxidant (e.g., m-CPBA), and rearrangement to thehalo-derivative by treatment of the N-oxide with a suitable reagent(e.g., PDX₃, RCOX, RSO₂X), which upon deprotection would furnishintermediates 10-2 (wherein X═Cl, Br, I). Halo-containing intermediate10-2 can serve as a substrate for introduction of substituent R².Substituent R² can be introduced, for example, via cross-coupling withR²-M, where M is a boronic acid, boronic ester, or an appropriatelysubstituted metal such as Sn(Bu)₄ or Zn, under standard Suzukiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., abicarbonate or carbonate base, or CsF)) or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to yieldintermediate 10-3. Alternatively, R² can be installed via nucleophilicaromatic substitution of the halogen of 10-2 with amines, for example,to provide 10-3 where R² is an amine. Halogenation of 10-3 using ahalogenating reagent (e.g. I₂, Br₂, N-chlorosuccinimideN-bromosuccinimide, or N-iodosuccinimide) can furnish intermediate 10-4(wherein X═Cl, Br, I). Formation of bicyclic intermediates 10-6 canproceed by treatment of amino heterocycles 10-4 with α-halo carbonylintermediates 10-5 (wherein X═Cl, Br), usually with heating and in thepresence of a suitable base (e.g., Na₂CO₃). Alternatively, theintermediate 10-5 may be in the form of the acetal or ketal, in whichcase reaction of such intermediate with 10-4 may include acid ratherthan base (e.g., p-toluenesulfonic acid). Conversion of the ester in10-6 to the ketone 10-7 can be performed as described in Scheme 3. Ifdesired, the halogen in 10-7 can be used as a handle for theintroduction of R⁶ via coupling with M-R⁶, where M is a boronic acid,boronic ester, or an appropriately substituted metal such as Sn(Bu)₄ orZn, under standard Suzuki conditions (e.g., in the presence of apalladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., abicarbonate or carbonate base, or CsF)) or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to yieldintermediate 10-8. Ketone 10-8 can be treated with one of the conditionsof Scheme 2 to provide an amine that can be converted to compounds ofthe invention 10-9 according to Scheme 1. It will be recognized by oneskilled in the art that the order of steps in Scheme 10 can be changedin consideration of compatibility of functional groups present in theintermediates.

Compounds of Formula I, wherein W═CH, X¹═C, X²═N, X³═CR³, X⁴═N and X⁵═N,can be prepared as shown in Scheme 11. Heteroaryl starting materials11-1 can be coupled with R²-M, where M is a boronic acid, boronic ester,or an appropriately substituted metal, such as Sn(Bu)₄ or Zn, understandard Suzuki conditions (e.g., in the presence of a palladiumcatalyst, such as tetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., abicarbonate or carbonate base, or CsF)) or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to yieldintermediates 11-2. Formation of the N-oxide using a suitable oxidant(e.g., m-CPBA), and rearrangement to the halo-derivative by treatment ofthe N-oxide with a suitable reagent (e.g., POX₃, RCOX, RSO₂X), canfurnish intermediate 11-3 (wherein X═Cl, Br). Nucleophilic aromaticsubstitution of the halide (i.e., group X) in intermediate 11-3 withhydrazine can afford intermediate 11-4. Acylation of 11-4 with 11-5,wherein CO-LG is a suitable carbonyl group (e.g., an acid chloride(LG═Cl) or anhydride (LG═O—(CO)R), or carboxylic acid in combinationwith a coupling agent (e.g., BOP, HATU, or EDO/HOBO and a base (e.g.,diisopropylethylamine)) can provide an acylhydrazide intermediate 11-6.Direct conversion of halide 11-3 to acylhydrazide intermediates 11-6 isalso possible by displacement of the halide of 11-3 directly with anacyl hydrazide (e.g., R³(CO)NHNH₂). A palladium-catalyzed cross couplingof an acyl hydrazide (e.g., R³(CO)NHNH₂) with heteroaryl halide 11-3(e.g., as described in Org. Lett. 2010, 12(4), p.792-795; usingPd₂(dba)₃, Josiphos, NaHCO₃ in DMF at elevated temperature) can alsoprovide 11-6 directly from intermediate 11-3. The intermediate 11-6 canbe cyclized to form bicyclic intermediate 11-7 under cyclo-dehydratingconditions (e.g. by heating in POCl₃ or by treatment with P₂O₅, SOCl₂ orwith acid). Alternatively, hydrazine containing intermediate 11-4 can beheated with orthoesters (e.g., trimethylorthoformate,triethylorthoacetate, or R³C(OR)₃), often under acid catalysis (e.g.,p-toluenesulfonic acid) to furnish 11-7 directly. If desired, R⁶ can beintroduced into the compound 11-7 via cross-coupling with R⁶-M, where Mis a boronic acid, boronic ester, or an appropriately substituted metalsuch as Sn(Bu)₄ or Zn, under standard Suzuki conditions (e.g., in thepresence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., abicarbonate or carbonate base, or CsF)) or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to affordintermediate 11-8. Conversion of the ester 11-8 to the ketone 11-9 canbe performed as described in Scheme 3. Ketone 11-9 can be treated withone of the conditions of Scheme 2 to provide an amine that can beconverted to compounds of the invention 11-10 according to Scheme 1. Itwill be recognized by one skilled in the art that the order of steps inScheme 11 can be changed in consideration of compatibility of functionalgroups present in the intermediates.

Compounds of Formula I, wherein Z¹═C, Z²═N, X³═N, X⁴═CR⁴, X⁵═CR⁵ canalso be synthesized as shown in Scheme 12. Heteroaryl starting materials12-1 can be aminated with an electrophilic amination reagent such as2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene, to form a N-aminoheterocycle of formula 12-2. Compound 12-2 is then reacted with asuitable acetylene 12-3 to form a heterocycle of formula 12-4.Halogenation (e.g., NCS) then affords intermediates 12-5, which canundergo cross coupling with tributylstannyl vinyl ethers under standardStille conditions (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0), in addition to a basesuch as CsF) to furnish intermediates 12-7 after hydrolysis.Nucleophilic aromatic substitution with ammonia, followed byhalogenation then affords 12-9. Sandmeyer reaction (e.g., NaNO₂, HCl,AcOH) provides compounds of formula 12-10, which can be decarboxylated(e.g., hydrolysis with aq. HCl followed by decarboxylation) to giveintermediates 12-11. Halogenation (e.g., NCS) or cyanation (e.g.,treatment with ClSO₂NCO followed by DMF) affords compounds of formula12-12. One method for introduction of R² is via selective cross-couplingwith R²-M, where M is a boronic acid, boronic ester, or an appropriatelysubstituted metal such as Sn(Bu)₄ or Zn, under standard Suzukiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., abicarbonate or carbonate base, or CsF)) or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to yieldintermediates 12-13. Ketones 12-13 can be treated with one of theconditions of Scheme 2 to provide an amine that can be converted tocompounds of the invention 12-14 according to Scheme 1. Alternatively,NR₂ can be installed via nucleophilic aromatic substitution of thehalogen of 12-12 with amines. Intermediates 12-15 can be treated withone of the conditions of Scheme 2 to provide an amine that can beconverted to compounds of the invention 12-16 according to Scheme 1.

Compounds of the Formula I wherein W=C—H, Z¹═C, Z²═N, X³═N, X⁴═N, X⁵═CR⁵can be prepared as shown in Scheme 13. Heteroaryl starting materials13-1 can be coupled with R²-M, where M is a boronic acid, boronic ester,or an appropriately substituted metal such as Sn(Bu)₄ or Zn, understandard Suzuki conditions (e.g., in the presence of a palladiumcatalyst, such as tetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., abicarbonate or carbonate base, or CsF)) or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to yieldintermediates 13-2. Formation of the N-oxide using a suitable oxidant(e.g., m-CPBA), and rearrangement to the halo-derivative by treatment ofthe N-oxide with a suitable reagent (e.g., PDX₃, RCOX, RSO2X), wouldfurnish intermediate 13-3 (wherein X═Cl, Br). Cross coupling with avinyl metal species 13-4 such as vinyltributylstannane, followed byoxidative cleavage of the olefin (e.g., OsO₄, NaIO₄) would affordaldehyde 13-5. Formation of the hydrazide gives 13-6, and oxidativecyclization with a suitable reagent such as MnO₂ or PhI(OAc)₂ thenaffords triazole 13-7. The halogen can optionally be cross coupled withR⁶-M to provide intermediates 13-8. Selective deprotonation of thetriazole ring with a strong base such as LiTMP and reaction with anelectrophilic halogen source (e.g., I₂) would afford 13-9. The halogencan optionally be cross coupled with R⁵-M to give compounds 13-10.Conversion of the ester in 13-10 to the ketone 13-11 can be performed asdescribed in Scheme 3. Ketones 13-11 can be treated with one of theconditions of Scheme 2 to provide an amine that can be converted tocompounds of the invention 13-12 according to Scheme 1.

Compounds of the Formula I wherein W═C—H, Z¹═C, Z²═N, X³═N, X⁴═N, X⁵═CR⁵can be prepared as shown in Scheme 14. Nitro-containing startingmaterials 1-1 can be reduced to the aniline 1-2. Cyclization of 1-2 witha reagent such as amyl nitrite can give indazole 1-3. Demethylation of1-3 using BBr₃ or a strong acid can give the phenol 1-4. Phenol 1-4 canbe converted to the triflate 1-5 under standard conditions with triflicanhydride. Protection of the indazole nitrogens can be accomplished togive 1-6 along with its regioisomer. Displacement of the triflate withan appropriate amine can give 1-7. The ketone in 1-7 can be converted toan amine by various methods as shown in Scheme 3 to furnish amine 1-8.Amine 1-8 can be coupled with an optionally protected carboxylic acidsuch as 1-2 (Scheme 1) by various methods as shown in Scheme 1. Aftercoupling, any chosen protecting groups can be removed under conditionssuitable for their removal, that are also compatible with thefunctionality present in the resulting compounds of the Formula I. Itwill be recognized by one skilled in the art that the order of steps inScheme 14 can be changed in consideration of compatibility of functionalgroups present in the intermediates.

The reactions for preparing compounds described herein can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,(e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature). A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

The expressions, “ambient temperature” and “room temperature” or “rt” asused herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Preparation of compounds described herein can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons,Inc., New York (1999).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) and normal phase silicachromatography.

Methods of Use

The compounds, salts or stereoisomers thereof described herein inhibitactivity of PI3Kγ kinase. Accordingly, the compounds, salts orstereoisomers described herein can be used in methods of inhibitingPI3Kγ kinase by contacting the kinase with any one or more of thecompounds, salts, or compositions described herein. In some embodiments,the compounds or salts can be used in methods of inhibiting activity ofPI3Kγ in an individual in need of said inhibition by administering ainhibiting amount of a compound or salt of described herein. In someembodiments, modulating is inhibiting. In some embodiments, thecontacting is in vivo. In some embodiments, the contacting is ex vivo.

In some embodiments, the PI3Kγ includes a mutation. A mutation can be areplacement of one amino acid for another, or a deletion of one or moreamino acids. In such embodiments, the mutation can be present in thekinase domain of the PI3Kγ.

In some embodiments, the compound or salt further inhibits PI3Kδ.

The compounds or salts described herein can be selective. By “selective”is meant that the compound binds to or inhibits PI3Kγ with greateraffinity or potency, respectively, compared to at least one otherkinase. In some embodiments, the compounds of the invention areselective inhibitors of PI3Kγ over PI3Kδ, PI3Kα, and PI3Kβ. In someembodiments, the compounds of the invention are selective inhibitors ofPI3Kγ over PI3Kα and PI3Kγ. In some embodiments, selectivity can be atleast about 2-fold, 3-fold, 5-fold, 10-fold, at or 20-fold over PI3K6 asmeasured by the assays described herein. In some embodiments,selectivity can be tested at the K_(m) ATP concentration of each enzyme.In some embodiments, the selectivity of compounds of the invention canbe determined by cellular assays associated with particular PI3K kinaseactivity.

Another aspect of the present invention pertains to methods of treatinga kinase PI3Kγ-associated disease or disorder in an individual (e.g.,patient) by administering to the individual in need of such treatment atherapeutically effective amount or dose of one or more compounds of thepresent invention or a pharmaceutical composition thereof. API3Kγ-associated disease or disorder can include any disease, disorderor condition that is directly or indirectly linked to expression oractivity of the PI3Kγ, including overexpression and/or abnormal activitylevels.

In some embodiments, the disease or disorder is an autoimmune disease ordisorder, cancer, cardiovascular disease, or neurodegenerative disease.

In some embodiments, the disease or disorder is lung cancer (e.g.,non-small cell lung cancer), melanoma, pancreatic cancer, breast cancer,prostate cancer, liver cancer, color cancer, endometrial cancer, bladdercancer, skin cancer, cancer of the uterus, renal cancer, gastric cancer,or sarcoma. In some embodiments, the sarcoma is Askin's tumor, sarcomabotryoides, chondrosarcoma, Ewing's sarcoma, malignanthemangioendothelioma, malignant schwannoma, osteosarcoma, alveolar softpart sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcomaprotuberans, desmoid tumor, desmoplastic small round cell tumor,epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletalosteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST),hemangiopericytoma, hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma,liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheralnerve sheath tumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma,synovial sarcoma, or undifferentiated pleomorphic sarcoma.

In some embodiments, the disease or disorder is acute myeloid leukemia(e.g., acute monocytic leukemia), small lymphocyctic lymphoma, chroniclymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiplemyeloma, T-cell actute lymphoblasic leukemia (T-ALL), cutaneous T-celllymphoma, large granular lymphocytic leukemia, mature (peripheral)t-cell neoplasm (PTCL), anaplastic large cell lymphoma (ALCL), orlymphoblastic lymphoma. In some embodiments, the mature (peripheral)t-cell neoplasm (PTCL) is T-cell prolymphocytic leukemia, T-cellgranular lymphocytic leukemia, aggressive NK-cell leukemia, mycosisfungoides/Sezary syndrome, naplastic large cell lymphoma (T-cell type),enteropathy type T-cell lymphoma, adult T-cell leukemia/lymphoma, orangioimmunoblastic T-cell lymphoma In some embodiments, the anaplasticlarge cell lymphoma (ALCL) is systemic ALCL or primary cutaneous ALCL.

In some embodiments, the disease or disorder is Burkitt's lymphoma,acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin'slymphoma, Hodgkin's lymphoma, hairy cell leukemia, Mantle cell lymphoma,small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacyticlymphoma, extranodal marginal zone lymphoma, Waldenstrom'smacroglobulinemia, prolymphocytic leukemia, acute lymphoblasticleukemia, myelofibrosis, mucosa-associated lymphatic tissue (MALT)lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoidgranulomatosis, splenic marginal zone lymphoma, primary effusionlymphoma, intravascular large B-cell lymphoma, plasma cell leukemia,extramedullary plasmacytoma, smouldering myeloma (aka asymptomaticmyeloma), monoclonal gammopathy of undetermined significance (MGUS), ordiffuse large B cell lymphoma.

In some embodiments, the non-Hodgkin's lymphoma (NHL) is relapsed NHL,refractory NHL, recurrent follicular NHL, indolent NHL (iNHL), oraggressive NHL (aNHL).

In some embodiments, the diffuse large B cell lymphoma is activatedB-cell like (ABC) diffuse large B cell lymphoma, or germinal center Bcell (GCB) diffuse large B cell lymphoma.

In some embodiments, the Burkitt's lymphoma is endemic Burkitt'slymphoma, sporadic Burkitt's lymphoma, or Burkitt's-like lymphoma

In some embodiments, the disease or disorder is rheumatoid arthritis,multiple sclerosis, systemic lupus erythematous, asthma, allergy,pancreatitis, psoriasis, anaphylaxis, glomerulonephritis, inflammatorybowel disease (e.g., Crohn's disease and ulcerative colitis),thrombosis, meningitis, encephalitis, diabetic retinopathy, benignprostatic hypertrophy, myasthenia gravis, Sjögren's syndrome,osteoarthritis, restenosis, or atherosclerosis.

In some embodiments, disease or disorder is heart hypertropy, cardiacmyocyte dysfunction, chronic obstructive pulmonary disease (COPD),elevated blood pressure, ischemia, ischemia-reperfusion,vasoconstriction, anemia (e.g., hemolytic anemia, aplastic anemia, orpure red cell anemia), bacterial infection, viral infection, graftrejection, kidney disease, anaphylactic shock fibrosis, skeletal muscleatrophy, skeletal muscle hypertrophy, angiogenesis, sepsis, graftrejection, glomerulosclerosis, progressive renal fibrosis, idiopathicthrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis,systemic lupus erythematosus, lupus nephritis, pemphigus, or membranousnephropathy.

In some embodiments, the disease or disorder is Alzheimer's disease,central nervous system trauma, or stroke.

In some embodiments, the idiopathic thrombocytopenic purpura (ITP) isrelapsed ITP or refractory ITP.

In some embodiments, the vasculitis is Behcet's disease, Cogan'ssyndrome, giant cell arteritis, polymyalgia rheumatica (PMR), Takayasu'sarteritis, Buerger's disease (thromboangiitis obliterans), centralnervous system vasculitis, Kawasaki disease, polyarteritis nodosa,Churg-Strauss syndrome, mixed cryoglobulinemia vasculitis (essential orhepatitis C virus (HCV)-induced), Henoch-Schönlein purpura (HSP),hypersensitivity vasculitis, microscopic polyangiitis, Wegener'sgranulomatosis, or anti-neutrophil cytoplasm antibody associated (ANCA)systemic vasculitis (AASV).

The present invention further provides a compound described herein, or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound describedherein, or a pharmaceutically acceptable salt thereof, for thepreparation of a medicament for use in any of the methods describedherein.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a PI3K with a compound of the invention includesthe administration of a compound of the present invention to anindividual or patient, such as a human, having a PI3K, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the PI3K.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

As used herein, the term “treating” or “treatment” can refer to one ormore of (1) inhibiting the disease; for example, inhibiting a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., arresting further development of the pathology and/orsymptomatology); and (2) ameliorating the disease; for example,ameliorating a disease, condition or disorder in an individual who isexperiencing or displaying the pathology or symptomatology of thedisease, condition or disorder (i.e., reversing the pathology and/orsymptomatology) such as decreasing the severity of disease.

Combination Therapies

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors,chemokine receptor inhibitors, and phosphatase inhibitors, as well asBcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, cKit, IGF-1R, RAFand FAK kinase inhibitors such as, for example, those described in WO2006/056399. Other agents such as therapeutic antibodies can be used incombination with the compounds of the present invention for treatment ofPI3K-associated diseases, disorders or conditions. The one or moreadditional pharmaceutical agents can be administered to a patientsimultaneously or sequentially.

In some embodiments, the compounds of the present disclosure can becombined with one or more inhibitors of the following kinases for thetreatment of cancer: Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC,CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2,HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II,KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea,TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2,EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK andB-Raf. In some embodiments, the compounds of the present disclosure canbe combined with one or more of the following inhibitors for thetreatment of cancer or infections. Non-limiting examples of inhibitorsthat can be combined with the compounds of the present disclosure fortreatment of cancer and infections include an FGFR inhibitor (FGFR1,FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 and INCB63904), a JAKinhibitor (JAK1 and/or JAK2, e.g., ruxolitinib, baricitinib orINCB39110), an IDO inhibitor (e.g., epacadostat and NLG919), an LSD1inhibitor (e.g., INCB59872 and INCB60003), a TDO inhibitor, a PI3K-deltainhibitor (e.g., INCB50797 and INCB50465), a Pim inhibitor, a CSF1Rinhibitor, a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), anangiogenesis inhibitor, an interleukin receptor inhibitor, bromo andextra terminal family members inhibitors (for example, bromodomaininhibitors or BET inhibitors such as INCB54329 and INCB57643) and anadenosine receptor antagonist or combinations thereof.

In some embodiments, the compound or salt described herein isadministered with a PI3Kδ inhibitor. In some embodiments, the compoundor salt described herein is administered with a JAK inhibitor. In someembodiments, the compound or salt described herein is administered witha JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In someembodiments, the compound or salt described herein is administered witha JAK1 inhibitor. In some embodiments, the compound or salt describedherein is administered with a JAK1 inhibitor, which is selective overJAK2.

Example antibodies for use in combination therapy include but are notlimited to Trastuzumab (e.g. anti-HER2), Ranibizumab (e.g. anti-VEGF-A),Bevacizumab (trade name Avastin, e.g. anti-VEGF, Panitumumab (e.g.anti-EGFR), Cetuximab (e.g. anti-EGFR), Rituxan (anti-CD20) andantibodies directed to c-MET.

One or more of the following agents may be used in combination with thecompounds of the present invention and are presented as a non limitinglist: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol,etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel,epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide,cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa,Tarceva, antibodies to EGFR, Gleevec™, intron, ara-C, adriamycin,cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17.alpha.-Ethinylestradiol, Diethylstilbestrol, Testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Fulvestrant, Ifosfomide, Rituximab, C225, Campath, Clofarabine,cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine,Smll, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP,and MDL-101,731.

Additional examples of chemotherapeutics include proteosome inhibitors(e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents suchas melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include corticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include the compounds, and pharmaceuticallyacceptable salts thereof, of the genera and species disclosed in U.S.Pat. No. 5,521,184, WO 04/005281, and U.S. Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 03/037347, WO03/099771, and WO 04/046120.

Example suitable RAF inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO05/028444.

Example suitable FAK inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 04/080980, WO04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO 01/014402.

In some embodiments, the compounds of the invention can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the compounds of the invention can be used incombination with a chemotherapeutic in the treatment of cancer, and mayimprove the treatment response as compared to the response to thechemotherapeutic agent alone, without exacerbation of its toxic effects.In some embodiments, the compounds of the invention can be used incombination with a chemotherapeutic provided herein. For example,additional pharmaceutical agents used in the treatment of multiplemyeloma, can include, without limitation, melphalan, melphalan plusprednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib).Further additional agents used in the treatment of multiple myelomainclude Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. Additive orsynergistic effects are desirable outcomes of combining a PI3K inhibitorof the present invention with an additional agent.

In some embodiments, PI3Kγ inhibitors provided herein can be used incombination with one or more immune checkpoint inhibitors for thetreatment of cancer as described herein. In one embodiment, thecombination with one or more immune checkpoint inhibitors as describedherein can be used for the treatment of melanoma. Exemplary immunecheckpoint inhibitors include inhibitors against immune checkpointmolecules such as CD27, CD28, CD40, CD122, OX40, GITR, CD137, ICOS,A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-Ll andPD-L2. In some embodiments, the compounds provided herein can be used incombination with one or more agents selected from KIR inhibitors, TIGITinhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRbeta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule PD-1 inhibitor or a small molecule PD-L1 inhibitor.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibodyis pembrolizumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016.

In some embodiments, the compounds of the invention can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of ID01,TDO, or arginase. Examples of IDOL inhibitors include epacadostat andNGL919.

In some embodiments, the compounds of the invention can be used incombination with an inhibitor of JAK or PI3K8.

In some embodiments, the JAK inhibitor is selective for JAK1 and JAK1over JAK3 and TYK2. In some embodiments, the JAK inhibitor is selectivefor JAK1 over JAK2, JAK3, and TYK2. In some embodiments, the JAKinhibitor inhibit JAK1 preferentially over JAK2 (e.g., have a JAK1/JAK2IC₅₀ ratio >1). In some embodiments, the JAK inhibitor is about 10-foldmore selective for JAK1 over JAK2.

In some embodiments, the JAK inhibitor is3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile.In some embodiments, the JAK inhibitor is(3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(ruxolitinib; also known as INCB018424). Ruxolitinib has an ICso of lessthan 10 nM at 1 mM ATP (assay D) at JAK1 and JAK2.3—Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrileand ruxolitinib can be made by the procedure described in U.S. Pat. No.7,598,257 (Example 67), filed Dec. 12, 2006, which is incorporatedherein by reference in its entirety. In some embodiments, the inhibitorof JAK1 and/or JAK2 is(3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrilephosphoric acid salt. In some embodiments, the inhibitor of JAK1 and/orJAK2 is2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile(baricitinib; also known as INCB028050).

In some embodiments, the JAK inhibitor is a compound of Table A, or apharmaceutically acceptable salt thereof. The compounds in Table 1 areselective JAK1 inhibitors (selective over JAK2, JAK3, and TYK2). TheIC₅₀s obtained by the method of Assay D at 1 mM ATP.

TABLE A JAK1 IC₅₀ JAK2/ # Prep. Name Structure (nM) JAK1  1 US 2014/0121198 ((2R,5S)-5-{2- [(1R)-1-hydroxy- ethyl]-1H- imidazo[4,5-d]-thieno[3,2-b]- pyridin-1-yl}- tetrahydro-2H- pyran-2-yl)- acetonitrile

++ >10  2 US 2014/034 3030 4-[3-(cyano- methyl)-3-(3′,5′- dimethyl-1H,1′H-4,4′-bi- pyrazol-1-yl)- azetidin-1-yl]- 2.5-difluoro-N- [(1S)-2,2,2-trifluoro-1- methylethyl]- benzamide

+++ >10  3 US 2010/ 0298334 (Example 2)^(a) 3-[1-(6-chloro-pyridin-2-yl)- pyrrolidin-3- yl]-3-[4-(7H- pyrrolo[2,3-d]-pyrimidin-4-yl)- 1H-pyrazol-1- yl]propanenitrile

+ >10  4 US 2010/ 0298334 (Example 13c) 3-(1-[1,3]- oxazolo[5,4-b]pyridin-2- ylpyrrolidin-3- yl)-3-[4-(7H- pyrrolo[2,3-d]-pyrimidin-4-yl)- 1H-pyrazol-1- yl]propanenitrile

+ >10  5 US 2011/ 0059951 (Example 12) 4-[(4-{3-cyano- 2-[4-(7H-pyrrolo-[2,3-d]pyrimidin- 4-yl)-1H-pyrazol- 1-yl]propyl}- piperazin-1-yl)-carbonyl]-3- fluorobenzonitrile

+ >10  6 US 2011/ 0059951 (Example 13) 4-[(4-{3-cyano- 2-[3-(7H-pyrrolo-[2,3-d]pyrimidin- 4-yl)-1H-pyrrol- 1-yl]propyl}- piperazin-1-yl)-carbonyl]-3- fluorobenzonitrile

+ >10  7 US 2011/ 0224190 (Example 1) {1-{1-[3-Fluoro- 2-(trifluorometh-yl)isonicotinoyl]- piperidin-4-yl}- 3-[4-(7H- pyrrolo[2,3-d]-pyrimidin-4-yl)- 1H-pyrazol-1- yl]azetidin-3- yl}acetonitrile

+ >10  8 US 2011/ 0224190 (Example 154) 4-{3-(Cyano- methyl)-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4- yl)-1H-pyrazol- 1-yl]azetidin-1-yl}-N-[4-fluoro- 2-(trifluoro- methyl)phenyl]- piperidine-1- carboxamide

+ >10  9 US 2011/ 0224190 (Example 85) [3-[4-(7H- pyrrolo[2,3-d]-pyrimidin-4-yl)- 1H-pyrazol-1- yl]-1-(1-{[2- (trifluoromethyl)-pyrimidin-4-yl]- carbonyl}piperi- din-4-yl)azetidin- 3-yl]acetonitrile

+ >10 10 US 2012/ 0149681 (Example 7b) [trans-1-[4-(7H- pyrrolo[2,3-d]-pyrimidin-4-yl)- 1H-pyrazol-1- yl]-3-(4-{[2- (trifluoromethyl)-pyrimidin-4-yl]- carbonyl}pipera- zin-1-yl)cyclo- butyl]acetonitrile

+ >10 11 US 2012/ 0149681 (Example 157) {trans-3-(4-{[4- [(3-hydroxy-azetidin-1-yl- [methyl]-6-(tri- fluoromethyl)- pyridin-2-yl]-oxy}piperidin- 1-yl)-1-[4-(7H- pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1- yl]cyclobutyl}- acetonitrile

+ >10 12 US 2012/ 0149681 (Example 161) {trans-3-(4- {[4-{[(2S)-2-(hydroxymethyl)- pyrrolidin-1-yl]- methyl}-6- (trifluoromethyl)-pyridin-2-yl]- oxy}piperidin- 1-yl)-1-[4-(7H- pyrrolo[2,3-d]-pyrimidin-4-yl)- 1H-pyrazol-1- yl]cyclobutyl}- acetonitrile

+ >10 13 US 2012/ 0149681 (Example 162) {trans-3-(4- {[4-{[(2R)-2-(hydroxymethyl)- pyrrolidin-1-yl]- methyl}-6-(tri- fluoromethyl)-pyridin-2-yl]- oxy}piperidin-1- yl)-1-[4-(7H- pyrrolo[2,3-d]-pyrimidin-4-yl)- 1H-pyrazol-1- yl]cyclobutyl}- acetonitrile

+ >10 14 US 2012/ 0149682 (Example 20)^(b) 4-(4-{3-[(dimeth-ylamino)methyl]- 5-fluorophenoxy}- piperidin-1-yl)-3- [4-(7H-pyrrolo-[2,3-d]pyrimidin- 4-yl)-1H-pyrazol- 1-yl]butanenitrile

+ >10 15 US 2013/ 0018034 (Example 18) 5-{3-(cyanometh- yl)-3-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)- 1H-pyrazol-1- yl]azetidin-1-yl}-N-isopropylpyra- zine-2-carbox- amide

+ >10 16 US 2013/ 0018034 (Example 28) 4-{3-(cyano- methyl)-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4- yl)-1H-pyrazol- 1-yl}azetidin-1-yl}-2,5-difluoro- N-[(1S)-2,2,2- trifluoro-1- methylethyl]- benzamide

+ >10 17 US 2013/ 0018034 (Example 34) 5-{3-(cyanometh- yl)-3-[4-(1H-pyrrolo[2,3-b]- pyridin-4-yl)-1H- pyrazol-1-yl}- azetidin-1-yl}-N-isopropylpyra- zine-2-carbox- amide

+ >10 18 US 2013/ 0045963 (Example 45) {1-(cis-4-{[6-(2-hydroxyethyl)-2- (trifluoromethyl)- pyrimidin-4-yl)- oxy}cyclohexyl)-3-[4-(7H-pyrrolo- [2,3-d]pyrimidin- 4-yl)-1H-pyrazol- 1-yl]azetidin-3-yl}acetonitrile

+ >10 19 US 2013/ 0045963 (Example 65) {1-(cis-4-{[4- [(ethylamino)-methyl]-6-(tri- fluoromethyl)- pyridin-2-yl]- oxy}cyclohexyl)-3-[4-(7H-pyrrolo- [2,3-d]pyrimidin- 4-yl)-1H-pyrazol- 1-yl]azetidin-3-yl}acetonitrile

+ >10 20 US 2013/ 0045963 (Example 69) {1-{cis-4-{[4-(1- hydroxy-1-meth-ylethyl)-6-(tri- fluoromethyl)- pyridin-2-yl]- oxy}cyclohexyl)-3-[4-(7H-pyrrolo- [2,3-d]pyrimidin- 4-yl)-1H-pyrazol- 1-yl]azetidin-3-yl}acetonitrile

+ >10 21 US 2013/ 0045963 (Example 95) {1-(cis-4-{[4- {(3R)-3-hydroxy-pyrrolidin-1-yl]- methyl}-6-(tri- fluoromethyl)- pyridin-2-yl]-oxy}cyclohexyl)- 3-[4-(7H-pyrrolo- [2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]azetidin-3- yl}acetonitrile

+ >10 22 US 2013/ 0045963 (Example 95) {1-(cis-4-{[4- {[(3S)-3-hydroxy-pyrrolidin-1- yl]methyl}-6- (trifluoromethyl)- pyridin-2-yl]oxy}-cyclohexyl)-3-[4- (7H-pyrrolo[2,3- d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]-azetidin-3-yl}- acetonitrile

+ >10 23 US 2014/ 0005166 (Example 1) {trans-3-(4- {[4-({[(1S)-2-hydroxy-1-meth- ylethyl]amino}- methyl)-6-(tri- fluoromethyl)-pyridin-2-yl]- oxy}piperidin- 1-yl)-1-[4-(7H- pyrrolo-[2,3-d]-pyrimidin-4-yl)- 1H-pyrazol-1- yl]cyclobutyl}- acetonitrile

+ >10 24 US 2014/ 0005166 (Example 14) {trans-3-(4-{[4- ({[(2R)-2-hydroxypropyl]- amino}methyl)- 6-(trifluoro- methyl)pyridin-2-yl]oxy}piperidin- 1-yl)-1-[4-(7H- pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1- yl]cyclobutyl}- acetonitrile

+ >10 25 US 2014/ 0005166 (Example 15) {trans-3-(4- {[4-({[(2S)-2-hydroxypropyl]- amino}methyl)- 6-(trifluoro- methyl)pyridin-2-yl]oxy}piperi- din-1-yl)-1-[4- (7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol- 1-yl]cyclobutyl}- acetonitrile

+ >10 26 US 2014/ 0005166 (Example 20) {trans-3-(4-{[4-(2-hydroxyethyl)- 6-(trifluoro- methyl)pyridin-2- yl]oxy}piperidin-1-yl)-1-[4-(7H- pyrrolo[2,3-d]- pyrimidin-4-yl)- 1H-pyrazol-1-yl]cyclobutyl}- acetonitrile

+ >10 + means <10 nM (see Example D for assay conditions) ++ means ≤100nM (see Example D for assay conditions) +++ means ≤300 nM (see Examle Dfor assay conditions) ^(a)Data for enantiomer 1 ^(b)Data for enantiomer2

The PI3Kδ inhibitor can be selective. By “selective” is meant that thecompound binds to or inhibits a kinase with greater affinity or potency,respectively, compared to at least one other kinase. In someembodiments, the PI3K8 inhibitor is a selective inhibitors of PI3Kδ(e.g., over PI3Kα, PI3Kβ and PI3Kγ). In some embodiments, selectivitycan be at least about 2-fold, 5-fold, 10-fold, at least about 20-fold,at least about 50-fold, at least about 100-fold, at least about200-fold, at least about 500-fold or at least about 1000-fold.Selectivity can be measured by methods routine in the art. In someembodiments, selectivity can be tested at the K_(m) ATP concentration ofeach enzyme. In some embodiments, the selectivity of compounds describedherein can be determined by cellular assays associated with particularPI3K kinase activity.

In some embodiments, the inhibitor of PI3Kδ is a compound shown in TableB. The compounds of Table B have been tested in Assay C and shown to beinhibitors of PI3Kδ with the IC50s in Table B.

TABLE B PI3Kδ IC₅₀ # Prep. Name Structure (nM) 27  US 2011/0015212(Example 10) 7-(1-(9H-purin-6-yl- amino)ethyl)-6-(3- fluorophenyl)-3-methyl-5H-thiazolo- [3,2-a]pyrimidin-5- one

+ 28  US 2011/0015212 (Example 15) (S)-7-(1-(9H-purin-6-ylamino)ethyl)-6-(3- fluorophenyl)-3- methyl-5H-thiazolo-[3,2-a]pyrimidin-5- one

+ 29  US 2013/ 0059835 (Example 269) 4-[1-(4-amino-3- methyl-1H-pyrazolo-[3,4-d]- pyrimidin-1-yl)- ethyl]-6-chloro-2-{1-[(2S)-2-hydroxy- propyl]azetidin-3- yl}-3-methoxy- benzonitrile

+ 30  US 2013/ 0039833 (Example 268) 4-[1-(4-amino-3- methyl-1H-pyrazolo[3,4-d]- pyrimidin-1-yl)- ethyl]-6-chloro-2-[1-(2-hydroxyethyl)- azetidin-3-yl]-3- methoxybenzonitrile

+ 31  US 2013/ 0059835 (Example 314) 5-{3-[1-(4-amino- 3-methyl-1H-pyrazolo[3,4-d]- pyrimidin-1-yl)ethyl- 6-cyano-2-ethoxy-5-methylphenyl}-N,N- dimethylpyridine-2- carboxamide

+ 32a, 32b, 32c, 32d  US 2013/ 0059835 (Example 345-348 (fourdiastereomers)) Compound 32a, 32b, 32c, and 32d are Examples 345, 346,347, and 348 respectively 4-{3-[1-(4-amino- 3-methyl-1H-pyrazolo[3,4-d]- pyrimidin-1-yl)- ethyl]-5-chloro-2- ethoxy-6-fluoro-phenyl}pyrrolidin- 2-one

32a (++),  32b (+)   32c (+)   32d (+++) 33  US 2011/0183985 (Example17-single enantiomer) N-{1-[5-chloro-8- (3-fluorophenyl)-cinnolin-7-yl]ethyl}- 9H-purin-6-amine

+ 34  US 2012/ 0157430 4-chloro-3′-fluoro- 3-methyl-6-[1-(9H-purin-6-ylamino)- ethyl]biphenyl-2- carbonitrile

+++ + means <50 nM ++ means 50 nM to 200 nM +++ means 50 nM to 100 nM

In some embodiments, the inhibitor of PI3Kδ is selected from:

(S)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;

(R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;

(S)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;

(R)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;

N-{(1S)-1-[5-chloro-8-(3-fluorophenyl)cinnolin-7-yl]ethyl}-9H-purin-6-amine;

and pharmaceutically acceptable salts of any of the aforementioned.

In some embodiments, the inhibitor of PI3Kδ is selected from:

4-[(R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}-3-methoxybenzonitrile;

4-[1(R)-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1-(2-hydroxyethypazetidin-3-yl]-3-methoxybenzonitrile;

5-{3-[1(R)-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-ethoxy-5-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;

4-[(S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}-3-methoxybenzonitrile;

4-[1(S)-(4-amino-3-methyl-1H-pyrazolo-[3,4-d]pyrimidin-1-yl)ehtyl]-6-chloro-2-[1-(2-hydroxyethyl)azetidin-3-yl]-3-methoxybenzonitrile;

5-{3-[1(S)-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-ethoxy-5-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;

and pharmaceutically acceptable salts of any of the aforementioned.

In some embodiments, PI3Kγ inhibitors provided herein can beadministered in combination with an inhibitor of JAK1 and/or JAK2 or aninhibitor of PI3Kδ.

The agents can be combined with the present compound in a single orcontinuous dosage form, or the agents can be administered simultaneouslyor sequentially as separate dosage forms.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the compounds of theinvention where the dexamethasone is administered intermittently asopposed to continuously.

In some further embodiments, combinations of the compounds of theinvention with other therapeutic agents can be administered to a patientprior to, during, and/or after a bone marrow transplant or stem celltransplant.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump.

Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

In some embodiments, the compositions of the invention contain fromabout 5 to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 5 to about 10, about 10 to about 15, about 15 to about20, about 20 to about 25, about 25 to about 30, about 30 to about 35,about 35 to about 40, about 40 to about 45, or about 45 to about 50 mgof the active ingredient.

In some embodiments, the compositions of the invention contain fromabout 50 to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 50 to about 100, about 100 to about 150, about 150 toabout 200, about 200 to about 250, about 250 to about 300, about 350 toabout 400, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions of the invention contain fromabout 500 to about 1000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 500 to about 550, about 550 to about 600, about 600 toabout 650, about 650 to about 700, about 700 to about 750, about 750 toabout 800, about 800 to about 850, about 850 to about 900, about 900 toabout 950, or about 950 to about 1000 mg of the active ingredient.

Similar dosages may be used of the compounds described herein in themethods and uses of the invention.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the invention. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the invention can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted herein.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating PI3K in tissue samples,including human, and for identifying PI3K ligands by inhibition bindingof a labeled compound. Accordingly, the present invention includes PI3Kassays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide that isincorporated in the instant radio-labeled compounds will depend on thespecific application of that radio-labeled compound. For example, for invitro PI3K labeling and competition assays, compounds that incorporate³H, ¹⁴C, ⁸²Br, ¹²⁵I , ¹³¹I, ³⁵S or will generally be most useful. Forradio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Bror ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind a PI3K by monitoring its concentrationvariation when contacting with the PI3K, through tracking of thelabeling. For example, a test compound (labeled) can be evaluated forits ability to reduce binding of another compound which is known to bindto a PI3K (i.e., standard compound). Accordingly, the ability of a testcompound to compete with the standard compound for binding to the PI3Kdirectly correlates to its binding affinity. Conversely, in some otherscreening assays, the standard compound is labeled and test compoundsare unlabeled.

Accordingly, the concentration of the labeled standard compound ismonitored in order to evaluate the competition between the standardcompound and the test compound, and the relative binding affinity of thetest compound is thus ascertained.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of PI3K-associated diseases ordisorders, such as cancer, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention. Such kits can furtherinclude, if desired, one or more of various conventional pharmaceuticalkit components, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Instructions,either as inserts or as labels, indicating quantities of the componentsto be administered, guidelines for administration, and/or guidelines formixing the components, can also be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to be PI3K₇inhibitors according to at least one assay described herein.

EXAMPLES

Preparatory LC-MS purifications of some of the compounds prepared wereperformed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature (see e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Hague, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004)). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity analysis under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm, 2.1×50 mm, Buffers: mobile phase A: 0.025% TFA in water and mobilephase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flowrate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature (see e.g.“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)). Typically, the flow rate used with the 30×100 mmcolumn was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.15% NH₄OH in water and mobile phase B:acetonitrile; the flow rate was 30 mL/minute, the separating gradientwas optimized for each compound using the Compound Specific MethodOptimization protocol as described in the literature (see e.g.“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)). Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results.

Example 1.2-amino-N-[1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. 1-(5-chloro-2-ethoxy-4-methyl-3-nitrophenyl)ethanone

To a solution of 1-(5-chloro-2-hydroxy-4-methyl-3-nitrophenypethanone(1.0 g, 4.4 mmol, from Oakwood) in DMF (10 mL) was added potassiumcarbonate (1.2 g, 8.7 mmol) and iodoethane (0.52 mL, 6.5 mmol), and thereaction mixture was heated to 60° C. for 1.5 h. After cooling to roomtemperature, the reaction mixture was partitioned between water (30 mL)and EtOAc (30 mL), and the layers were separated. The aqueous layer wasextracted with EtOAc (20 mL), and the combined organic layers were driedover MgSO₄, filtered, and concentrated. The residue was purified byflash chromatography on silica gel (0-20% EtOAc/hexanes) to afford thetitle compound (1.07 g, 95%) as a colorless oil. LCMS calculated forC₁₁H₁₃ClNO₄(M+H)⁺: m/z=258.0; found: 258.0.

Step 2. 1-(3-amino-5-chloro-2-ethoxy-4-methylphenyl)ethanone

To a solution of 1-(5-chloro-2-ethoxy-4-methyl-3-nitrophenypethanone(1.0 g, 3.9 mmol) in MeOH (10 mL) was added Pt/C (5 wt %, 200 mg, 0.04mmol). The atmosphere was replaced with hydrogen and the reactionmixture was stirred under balloon pressure of hydrogen overnight. Thereaction mixture was filtered through a pad of celite, which was washedwith additional MeOH (20 mL), and the volatiles were evaporated. Theresidue was purified by flash chromatography on silica gel (0-20%EtOAc/hexanes) to afford the product as a white solid (630 mg, 71%).LCMS calculated for C₁₁H₁₅ClNO₂(M+H)⁺: m/z=228.1; found: 228.1.

Step 3. 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanone

To a solution of 1-(3-amino-5-chloro-2-ethoxy-4-methylphenyl)ethanone(630 mg, 2.8 mmol) in AcOH (17 mL) was added amyl nitrite (0.41 mL, 3.0mmol) dropwise at room temperature. After stirring for 0.5 h, aprecipitate was observed, and the reaction mixture was heated to 110° C.for 1 h. The solution was cooled to room temperature and the volatileswere evaporated. The residue was azeotroped with toluene (50 mL) toremove any remaining AcOH. The resulting orange solid (630 mg, 95%) wasdried under high vacuum overnight and used without purification. LCMScalculated for C₁₁H₁₂ClN₂O₂(M+H)⁺: m/z=239.1; found: 239.1.

Step 4. 1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethanone

To a solution of 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanone (30.0 mg,0.126 mmol) in dry EtOAc (1 mL) was added trimethyloxoniumtetrafluoroborate (24 mg, 0.16 mmol) at room temperature. The suspensionwas heated to 40° C. until complete dissolution, and the resultingsolution was stirred at room temperature for 3 h. The solution wasdiluted with EtOAc (10 mL) and washed with saturated NaHCO₃ (5 mL). Theorganic layer was dried over MgSO₄, filtered, and concentrated, and theresulting solid was purified by flash chromatography (0-30%EtOAc/hexanes) to afford the title compound as a white solid (27.1 mg,85%). LCMS calculated for C₁₂H₁₄ClN₂O₂ (M+H)⁺: m/z=253.1; found: 253.1.

Step 5. 1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethanamine

A solution of 1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethanone(27.1 mg, 0.107 mmol) and ammonium acetate (120 mg, 1.6 mmol) in MeCN (1mL) and MeOH (1 mL) was heated at 65° C. for 0.5 h. The solution wascooled to room temperature, and sodium cyanoborohydride (17 mg, 0.27mmol) was added. The reaction mixture was heated to 65° C. overnight.The solution was cooled to room temperature, diluted with EtOAc (10 mL),and quenched with sat. NaHCO₃ (5 mL). The layers were separated and theaqueous layer was extracted with EtOAc (10 mL). The combined organiclayers were dried over MgSO₄, filtered, and concentrated, and theproduct was used without purification (theoretical yield assumed). LCMScalculated for C₁₂H₁₄ClN₂O (M−NH₂)⁺: m/z=237.1; found: 237.1.

Step 6. teat-butyl3-(1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate

To a vial containing1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethanamine (27.2 mg, 0.107mmol, from Example 1, Step 5),2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (39 mg, 0.14 mmol, from J&W Pharmlab), andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (53 mg, 0.14 mmol) was added DMF (2 mL), followed bydropwise addition of N,N-diisopropylethylamine (0.037 mL, 0.21 mmol) atroom temperature. After stirring for 1 h, the reaction mixture wasdiluted with EtOAc (10 mL) and quenched with water (5 mL). The layerswere separated, and the organic layer was dried over MgSO₄, filtered,and concentrated. The product was used without purification (theoreticalyield assumed). LCMS calculated for C₂₄H₂₉ClN₇O₄(M+H)⁺: m/z=514.2;found: 514.2.

Step 7.2-amino-N-[1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The tert-butyl3-(1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate(54 mg, 0.107 mmol, from Example 1, Step 6) was taken up in CH₂Cl₂ (2mL), and trifluoroacetic acid (0.6 mL, 7 mmol) was added at roomtemperature. After 1 h, the volatiles were evaporated. The residue wasdissolved in MeOH and purified by preparative HPLC (C-18 column elutingwith a water: acetonitrile gradient buffered at pH 2 with 0.1%trifluoroacetic acid) to give the title compound as a white solid. ¹HNMR (600 MHz, DMSO-d6) δ 8.91 (dd, J=6.7, 1.6 Hz, 1H), 8.55 (dd, J=4.5,1.7 Hz, 1H), 8.44 (s, 1H), 8.27 (d, J=8.1 Hz, 1H), 7.03 (s, 1H), 6.99(dd, J=6.7, 4.5 Hz, 1H), 5.51 (p, J=7.0 Hz, 1H), 4.70-4.59 (m, 2H), 4.19(s, 3H), 1.50 (d, J=7.0 Hz, 3H), 1.41 (t, J=7.0 Hz, 3H); LCMS calculatedfor C₁₉H₂₀ClN₇O₂Na (M+Na)⁺: m/z=436.1; found: 436.1.

Example 2.2-amino-N-[1-(4-chloro-7-ethoxy-2-ethyl-2H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

This compound was synthesized according to the procedure described forExample 1, substituting triethyloxonium tetrafluoroborate instead oftrimethyloxonium tetrafluoroborate in Step 4. ¹H NMR (600 MHz, DMSO-d6)δ 8.91 (dd, J=6.7, 1.6 Hz, 1H), 8.55 (dd, J=4.5, 1.7 Hz, 1H), 8.48 (s,1H), 8.28 (d, J=8.1 Hz, 1H), 7.03 (s, 1H), 6.99 (dd, J=6.7, 4.5 Hz, 1H),5.50 (p, J=7.0 Hz, 1H), 4.69 (dq, J=9.6, 7.0 Hz, 1H), 4.63 (dq, J=9.6,7.2 Hz, 1H), 4.47 (q, J=7.3 Hz, 2H), 1.51 (t, J=7.2 Hz, 3H), 1.50 (d,J=7.2 Hz, 3H), 1.41 (t, J=7.0 Hz, 3H); LCMS calculated for C₂₀H₂₂ClN₇O₂(M+Na)⁺: m/z=450.1; found: 450.1.

Examples 3a & 3b.2-amino-N-[1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate (single enantiomers isolated)

Step 1. 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanamine

This compound was synthesized according to the procedure described inExample 1, Step 5, starting from1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethanone (450 mg, 1.9mmol, from Example 1, Step 3). LCMS calculated for C₁₁H₁₀ClN₁O (M−NH₂)⁺:m/z=223.1; found: 223.1.

Step 2. tert-butyl3-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate

This compound was synthesized according to the procedure described inExample 1, Step 6, starting with1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanamine (prepared in theprevious step). The product was purified by flash chromatography (0-100%EtOAc/hexanes) to afford the racemic title compound as an off whitesolid (560 mg, 59%). LCMS calculated for C₂₃H₂₇ClN₇O₄(M+H)⁺: m/z=500.2;found: 500.2. A fraction of this material (120 mg) was separated bychiral HPLC (Chiral Technologies Chiralcel AD-H, 5 μm, 20×250 mm,eluting with 20% EtOH/hexanes, 18 mL/min) to afford enantiomer 1 (firstto elute, retention time 8.4 min; 30 mg) and enantiomer 2 (second toelute, retention time 11.2 min; 30 mg).

Step 3.2-amino-N-[1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate (single enantiomers isolated)

After removal of solvent in vacuo, each enantiomer from Example 3, Step2 was deprotected separately by stirring with TFA (0.5 mL) in CH₂Cl₂ (2mL) for 0.5 h. The volatiles were removed in vacuo to afford the titlecompound as single enantiomers, which did not require purification.

Enantiomer 1 (Example 3a): ¹H NMR (600 MHz, DMSO-d6) δ 8.92 (dd, J=6.7,1.6 Hz, 1H), 8.56 (dd, J=4.5, 1.6 Hz, 1H), 8.19 (d, J=7.7 Hz, 1H), 8.11(s, 1H), 7.13 (s, 1H), 7.01 (dd, J=6.7, 4.5 Hz, 1H), 5.55 (p, J=7.0 Hz,1H), 4.29 (d, J=6.7 Hz, 2H), 1.52 (d, J=7.0 Hz, 3H), 1.46 (t, J=7.0 Hz,3H). LCMS calculated for C₁₈H₁₈ClN₇O₂(M+H)⁺: m/z=400.1; found: 400.2.Enantiomer 2 (Example 3b): LCMS calculated for C₁₈H₁₈ClN₇O₂(M+H)⁺:m/z=400.1; found: 400.2.

Example 4.2-amino-N-[1-(4-chloro-7-ethoxy-1-methyl-1H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. tert-butyl3-(1-(4-chloro-7-ethoxy-1-methyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate& tert-butyl3-(1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate

To a solution of tert-butyl[3-({[1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate(30 mg, 0.06 mmol, from Example 3, Step 2) in DMF (0.5 mL) was addedpotassium carbonate (16 mg, 0.12 mmol), followed by methyl iodide (6 μL,0.09 mmol) and the reaction mixture was heated to 60° C. for 3 h. Aftercooling to room temperature, the reaction mixture was diluted with EtOAc(10 mL) and washed with water (5 mL). The organic layer was dried overMgSO₄, filtered and concentrated, and the product was used withoutpurification. The title compounds were obtained in approximately a 1:1ratio. LCMS calculated for C₂₄H₂₉ClN₇O₄(M+H)⁺: m/z=514.2; found: 514.1.

Step 2.2-amino-N-[1-(4-chloro-7-ethoxy-1-methyl-1H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate &2-amino-N-(1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The deprotection was performed as described in Example 1, Step 7. Alongwith the desired indazole N1 regioisomer, the N2 regioisomer was alsoobtained in a ˜1:1 ratio. The residue was dissolved in MeOH and purifiedby preparative HPLC (C-18 column eluting with a water:acetonitrilegradient [37.4-57.4% acetonitrile] buffered at pH 2 with 0.1%trifluoroacetic acid). The title compounds were separable and each wasobtained as a white solid. N1 isomer (Example 4): Retention time=5.9min. LCMS calculated for C₁₉H₂₁ClN₇O₂(M+H)⁺: m/z=414.1; found: 414.1. N2isomer (Example 1): Retention time=4.9 min.

Examples 5-13 were synthesized via an alkylation with the appropriatealkyl halide and subsequent deprotection as described for Example 4. Ineach case, the alkylation step afforded a varying mixture of N1 and N2indazole regioisomers. These isomers were separable by preparative HPLCafter deprotection, unless otherwise noted. The N1 regioisomers preparedand the corresponding data are listed in Table 1. The N2 regioisomersprepared and the corresponding data are listed in Table 2.

TABLE 1

Ex. No. Name R = LCMS ¹H NMR  5 2-amino-N-{1-[4-chloro-7-ethoxy-1-(2-methoxy- ethyl)-1H-indazol-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carbox- amide trifluoroacetate

Calculated for C₂₁H₂₅ClN₇O₃ (M + H)⁺: m/z = 458.2; found: 458.2  62-amino-N-(1-(4-chloro- 7-ethoxy-1-(2-hydroxy- ethyl)-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carbox- amide trifluoroacetate

Calculated for C₂₀H₂₃ClN₇O₃ (M + H)⁺: m/z = 444.2; found: 444.2  72-amino-N-(1-(4-chloro- 1-cyanomethyl)-7- ethoxy-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carbox- amide trifluoroacetate

Calculated for C₂₀H₂₀ClN₈O₂ (M + H)⁺: m/z = 439.1; found: 439.2 1H NMR(600 MHz, DMSO- d₆) δ 8.93 (dd, J = 6.7, 1.6 Hz, 1H), 8.57 (dd, J = 4.5,1.6 Hz, 1H), 8.28 (s, 1H), 8.17 (d, J = 7.2 Hz, 1H), 7.31 (s, 1H), 7.02(dd, J = 6.7, 4.5 Hz, 1H), 5.84- 5.69 (m, 2H), 5.53 (p, J = 6.9 Hz, 1H),4.46-4.32 (m, 1H), 4.12 (dq, J = 9.2, 7.0 Hz, 1H), 1.54 (t, J = 6.8 Hz,6H).  8 2-amino-N-(1-(1-benzyl- 4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)- pyrazolo[1,5-a]pyrim- idine-3-carboxamidetrifluoroacetate

Calculated for C₂₅H₂₅ClN₇O₂ (M + H)⁺: m/z = 490.2; found: 490.2  92-amino-N-(1-(4-chloro- 7-ethoxy-1-isobutyl-1H- indazol-6-yl)ethyl)-pyrazolo[1,5-a]pyrim- idine-3-carboxamide trifluoroacetate

Calculated for C₂₂H₂₇ClN₇O₂ (M + H)⁺: m/z = 456.2; found: 456.2 102-amino-N-(1-(4-chloro- 1-cyclobutyl-7-ethoxy- 1H-indazol-6-yl)ethyl)-pyrazolo[1,5-a]pyrim- idine-3-carboxamide

Calculated for C₂₂H₂₅ClN₇O₂ (M + H)⁺: m/z = 454.2; found: 454.2trifluoroacetate 11 2-amino-N-(1-(4-chloro- 7-ethoxy-1-isopropyl-1H-indazol-6-yl)ethyl)- pyrazolo[1,5-a]pyrim- idine-3-carboxamide

Calculated for C₂₁H₂₅ClN₇O₂ (M + H)⁺: m/z = 442.2; found: 442.1trifluoroacetate

TABLE 2

Ex. No. Name R = LCMS ¹H NMR  5a 2-amino-N-(1-(4-chloro-7-ethoxy-2-(2-methoxy- ethyl)-2H-indazol-6-yl)- ethyl)pyrazolo[1,5-a]-pyrimidine-3-carbox- amide trifluoroacetate

Calculated for C₂₁H₂₅ClN₇O₃ (M + H)⁺: m/z = 458.2; found: 458.2 ¹H NMR(600 MHz, DMSO- d6) δ 8.91 (dd, J = 6.7, 1.6 Hz, 1H), 8.55 (dd, J = 4.5,1.6 Hz, 1H), 8.44 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 6.99(dd, J = 6.7, 4.5 Hz, 1H), 5.50 (p, J = 7.0 Hz, 1H), 4.71-4.62 (m, 2H),4.61 (dd, J = 6.4, 4.0 Hz, 2H), 3.83 (t, J = 10.2, 5.4 Hz, 2H), 3.23 (s,3H), 1.51 (d, J = 7.0 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H).  6a2-amino-N-(1-(4-chloro- 7-ethoxy-2-(2-hydroxy- ethyl)-2H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carbox- amide trifluoroacetate

Calculated for C₂₀H₂₃ClN₇O₃ (M + H)⁺: m/z = 444.2; found: 444.2 ¹H NMR(600 MHz, DMSO- d6) δ 8.91 (dd, J = 6.7, 1.6 Hz, 1H), 8.55 (dd, J = 4.5,1.6 Hz, 1H), 8.42 (s, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.03 (s, 1H), 6.99(dd, J = 6.7, 4.5 Hz, 1H), 5.50 (p, J = 7.0 Hz, 1H), 4.69 (dq, J = 9.6,7.0 Hz, 1H), 4.63 (dq, J = 9.6, 7.0 Hz, 1H), 4.48 (t, J = 5.4 Hz, 2H),3.87 (t, J = 5.4 Hz, 2H), 1.50 (d, J = 7.0 Hz, 3H), 1.41 (t, J = 7.0 Hz,3H).  7a 2-amino-N-(1-(4-chloro- 2-(cyanomethyl)-7- ethoxy-2H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carbox- amide trifluoroacetate

Calculated for C₂₀H₂₀ClN₈O₂ (M + H)⁺: m/z = 439.1; found: 439.2    8a2-amino-N-(1-(2-benzyl- 4-chloro-7-ethoxy-2H- indazol-6-yl)ethyl)-pyrazolo[1,5-a]pyrim- idine-3-carboxamide trifluoroacetate

Calculated for C₂₅H₂₅ClN₇O₂ (M + H)⁺: m/z = 490.2; found: 490.2 ¹H NMR(600 MHz, DMSO- d6) δ 8.91 (dd, J = 6.7, 1.6 Hz, 1H), 8.60 (s, 1H), 8.54(dd, J = 4.5, 1.6 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 7.39-7.28 (m, 5H),7.05 (s, 1H), 6.99 (dd, J = 6.7, 4.5 Hz, 1H), 5.68 (s, 2H), 5.49 (p, J =7.0 Hz, 1H), 4.66 (dq, J = 9.8, 7.1 Hz, 1H), 4.63-4.58 (m, 1H), 1.49 (d,J = 7.0 Hz, 3H), 1.39 (t, J = 7.0 Hz, 3H).  9a 2-amino-N-(1-(4-chloro-7-ethoxy-2-isobutyl-2H- indazol-6-yl)ethyl)- pyrazolo[1,5-a]pyrim-idine-3-carboxamide trifluoroacetate

Calculated for C₂₂H₂₇ClN₇O₂ (M + H)⁺: m/z = 456.2; found: 456.2 ¹H NMR(600 MHz, DMSO- d6) δ 8.91(dd, J = 6.7, 1.6 Hz, 1H), 8.55 (dd, J = 4.5,1.6 Hz, 1H), 8.45 (s, 1H), 8.28 (d, J = 8.1 Hz, 1H), 7.03 (s, 1H), 6.99(dd, J = 6.7, 4.5 Hz, 1H), 5.50 (p, J = 7.0 Hz, 1H), 4.68 (dq, J = 9.6,7.0 Hz, 1H), 4.63 (dq, J = 9.6. 7.0 Hz, 1H), 4.25 (d, J = 7.2 Hz, 2H),2.29 (hept, J = 6.8 Hz, 1H), 1.51 (d, J = 7.0 Hz, 3H), 1.41 (t, J = 7.0Hz, 3H), 0.87 (dd, J = 6.7, 3.7 Hz, 6H). 10a 2-amino-N-(1-(4-chloro-2-cyclobutyl-7-ethoxy- 2H-indazol-6-yl)ethyl)- pyrazolo[1,5-a]pyrim-idine-3-carboxamide

Calculated for C₂₂H₂₅ClN₇O₂ (M + H)⁺: m/z = 454.2; found: 454.2 ¹H NMR(600 MHz, DMSO- d6) δ 8.91 (dd, J = 6.7, 1.6 Hz, 1H), 8.55 (dd, J = 4.5,1.7 Hz, 1H), 8.53 (s, 1H), 7.04 (s, 1H), 6.99 (dd, J = 6.7, 4.5 Hz, 1H),trifluoroacetate 5.50 (p, J = 7.0 Hz, 1H), 5.22- 5.14 (m, 1H), 4.72 (dq,J = 9.6, 7.0 Hz, 1H), 4.65 (dq, J = 9.7, 7.0 Hz, 1H), 2.67-2.59 (m, 2H),2.49 (m, 3H), 1.91- 1.83 (m, 3H), 1.50 (d, J = 7.0 Hz, 3H), 1.43 (t, J =7.0 Hz, 3H). 11a 2-amino-N-(1-(4-chloro- 7-ethoxy-2-isopropyl-2H-indazol-6-yl)ethyl)- pyrazolo[1,5-a]pyrim- idine-3-carboxamide

Calculated for C₂₁H₂₅ClN₇O₂ (M + H)⁺: m/z = 442.2; found: 442.1 ¹H NMR(600 MHz, DMSO- d6) δ 8.91 (dd, J = 6.7, 1.6 Hz, 1H), 8.55 (dd, J = 4.5,1.6 Hz, 1H), 8.49 (s, 1H), 8.28 (d, J = 8.1 Hz, 1H), 7.03 (s, 1H),trifluoroacetate 6.99 (dd, J = 6.7, 4.5 Hz, 1H), 5.50 (p, J = 7.0 Hz,1H), 4.85 (hept, J = 6.7 Hz, 1H), 4.71 (dq, J = 9.6, 7.0 Hz, 1H), 4.64(dq, J = 9.6, 7.0 Hz, 1H), 1.56 (d, J = 6.7 Hz, 6H), 1.50 (d, J = 7.0Hz, 3H), 1.42 (t, J = 7.0 Hz, 3H). 12  2-amino-N-(1-(2-(2-amino-2-oxoethyl)-4- chloro-7-ethoxy-2H- indazol-6-yl)ethyl)-pyrazolo[1,5-a]pyrim- idine-3-carboxamide trifluoroacetate

Calculated for C₂₀H₂₂ClN₈O₃ (M + H)⁺: m/z = 457.1; found: 457.2 ¹H NMR(600 MHz, DMSO- d6) δ 8.91 (dd, J = 6.7, 1.6 Hz, 1H), 8.55 (dd, J = 4.5,1.6 Hz, 1H), 8.43 (s, 1H), 8.27 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.38(s, 1H), 7.05 (s, 1H), 6.99 (dd, J = 6.7, 4.5 Hz, 1H), 5.51 (m, isolatedas an 1H), 5.13 (s, 2H), 4.65 (dq, inseparable 3:1 mixture J = 9.6, 7.1Hz, 1H), 4.60 (dq, of N2:N1 regioisomers; J = 9.5, 7.1 Hz, 1H), 1.51 (t,NMR data reported is J = 7.0 Hz, 3H), 1.40 (t, J = for N2 isomer (major)7.0 Hz, 3H). 13  2-amino-N-(1-(2-(but-2- ynyl)-4-chloro-7-ethoxy-2H-indazol-6-yl)ethyl)- pyrazolo[1,5-a]pyrim- idine-3-carboxamidetrifluoroacetate isolated as an inseparable 3:1 mixture of N2:N1regioisomers:

Calculated for C₂₂H₂₃ClN₇O₂ (M + H)⁺: m/z = 452.2; found: 452.2 ¹H NMR(600 MHz, DMSO- d6) δ 8.90 (dd, J = 6.7, 1.6 Hz, 1H), 8.54 (dd, J = 4.5,1.6 Hz, 1H), 8.49 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.07 (s, 1H), 6.99(dd, J = 6.7, 4.5 Hz, 1H), 5.51 (p, J = 7.0 Hz, 1H), 5.33 (q, J = 2.3Hz, 2H), 4.67 (dq, J = 9.6, 7.0 Hz, 1H), 4.62 (dq, 9.6, NMR datareported is 7.0 Hz, 1H), 1.86 (t, J = 2.5 for N2 isomer (major) Hz, 3H),1.51 (d, J = 7.0 Hz, 3H), 1.42 (t, J = 7.0 Hz, 3H).

Example 14.2-amino-N-(1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. 6-acetyl-4-chloro-3-methyl-2-nitrophenyltrifluoromethanesulfonate

Trifluoromethanesulfonic anhydride (1M/CH₂Cl₂, 13 mL, 13 mmol) was addedto a solution of 1-(5-chloro-2-hydroxy-4-methyl-3-nitrophenypethanone(2.0 g, 8.7 mmol, from Oakwood) and triethylamine (2.4 mL, 17 mmol) inTHF (20 mL) at −78° C. The solution was allowed to warm to roomtemperature and stirred for 0.5 h. The reaction mixture was diluted withEtOAc (30 mL) and quenched with sat. NaHCO₃ (20 mL). The layers wereseparated and the organic layer was washed with sat. NaCl (20 mL), driedover MgSO₄, filtered, and concentrated. The residue was purified byflash chromatography on silica gel (O-15% EtOAc/hexanes) to afford theproduct as an orange oil (3.2 g, 100%). LCMS calculated forC₁₀H₈ClF₃NO₆S (M+H)⁺: m/z=362.0; found: 361.8.

Step 2. 1-(4-chloro-5-methyl-6-nitrobiphenyl-2-yl)ethanone

To a solution of 6-acetyl-4-chloro-3-methyl-2-nitrophenyltrifluoromethanesulfonate (3.2 g, 8.8 mmol) in toluene (20 mL) was addeda solution of sodium bicarbonate (1.4 g, 17 mmol) in water (20 mL),followed by phenylboronic acid (1.2 g, 10.0 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.48 g, 0.41 mmol). Nitrogenwas bubbled through the solution for 5 min, and the reaction mixture washeated at 80° C. (bath temp) for 2 h. The reaction mixture was dilutedwith EtOAc (30 mL), the layers were separated and the organic layer waswashed with saturated NaCl (20 mL), dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography on silicagel (0-10% EtOAc/hexanes) to afford the title compound as a white solid(2.3 g, 88%). LCMS calculated for C₁H₁₃ClNO₃(M+H)⁺: m/z=290.1; found:290.0.

Step 3. 1-(6-amino-4-chloro-5-methylbiphenyl-2-yl)ethanone

This compound was synthesized according to the procedure described inExample 1, Step 2, starting from1-(4-chloro-5-methyl-6-nitrobiphenyl-2-yl)ethanone (2.25 g, 7.77 mmol).The crude product was purified by flash chromatography on silica gel(0-20% EtOAc/hexanes) to afford the title compound as a white solid(1.57 g, 78%). LCMS calculated for C₁₅H₁₅ClNO (M+H)⁺: m/z=260.1; found:260.0.

Step 4. 1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethanone

This compound was synthesized according to the procedure described inExample 1, Step 3, starting from1-(6-amino-4-chloro-5-methylbiphenyl-2-ypethanone (1.57 g, 6.04 mmol).The product was obtained as an orange solid (1.64 g, 100%). LCMScalculated for C₁₅H₁₂ClN₂O (M+H)⁺: m/z=271.1; found: 271.0.

Step 5. 1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethanamine

This compound was synthesized according to the procedure described inExample 1, Step 5, starting from1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethanone (591 mg, 2.18 mmol). Theproduct was used without purification (theoretical yield assumed). LCMScalculated for C₁₅H₁₂ClN₂ (M−NH₂)⁺: m/z=255.1; found: 255.1.

Step 6. tert-butyl3-(1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate

This compound was synthesized according to the general proceduredescribed in Example 1, Step 6, starting from1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethanamine (593 mg, 2.18 mmol). Theproduct was purified by flash chromatography on silica gel (0-60%EtOAc/hexanes) to afford the title compound as an off white solid (562mg, 48%). LCMS calculated for C₂₇H₂₆ClN₇O₃(M+H)⁺: m/z=532.2; found:532.2.

Step 7.2-amino-N-(1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate p The deprotection was performed as described inExample 1, Step 7, starting from tert-butyl3-(1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate(10 mg, 0.020 mmol). The residue was dissolved in MeOH and purified bypreparative HPLC (C-18 column eluting with a water: acetonitrilegradient buffered at pH 2 with 0.1% trifluoroacetic acid) to give thetitle compound as a white solid. LCMS calculated for C₂₂H₁₉ClN₇O (M+H)⁺:m/z=432.1; found: 432.1. Examples 15 & 16.2-amino-N-(1-(4-chloro-1-methyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate &2-amino-N-(1-(4-chloro-2-methyl-7-phenyl-2H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. tert-butyl3-(1-(4-chloro-1-methyl-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate& tert-butyl3-(1-(4-chloro-2-methyl-7-phenyl-2H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate

This compound was synthesized according the procedure described inExample 4, Step 1, starting with tert-butyl3-(1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate(30 mg, 0.060 mmol, from Example 14, Step 6). The title compounds wereobtained in ˜1:1.5 of N2:N1 regioisomers. The products were used withoutpurification (theoretical yield assumed). Peak 1: LCMS calculated forC₂₈H₂₉ClN₇O₃ (M+H)⁺: m/z=546.2; found 546.2. Peak 2: LCMS calculated forC₂₈H₂₉ClN₇O₃ (M+H)⁺: m/z=546.2; found 546.3.

Step 2.2-amino-N-(1-(4-chloro-1-methyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate &2-amino-N-(1-(4-chloro-2-methyl-7-phenyl-2H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The deprotection was performed as described in Example 1, Step 7,starting from a 1:1.5 mixture of tert-butyl3-(1-(4-chloro-1-methyl-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamateand tert-butyl3-(1-(4-chloro-2-methyl-7-phenyl-2H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate(32.7 mg, 0.060 mmol). The residue was dissolved in MeOH and purified bypreparative HPLC (C-18 column eluting with a water:acetonitrile gradient[38.5-58.5% acetonitrile] buffered at pH 2 with 0.1% trifluoroaceticacid). The title compounds were separable and each was obtained as awhite solid. Peak 1 (Example 16): Retention time=5.6 min. LCMScalculated for C₂₃H₂₁ClN₇O (M+H)⁺: m/z=446.1; found: 446.2. Peak 2(Example 15): Retention time=7.0 min. ¹H NMR (600 MHz, DMSO-d6) δ 8.91(dd, J=6.7, 1.6 Hz, 1H), 8.56 (dd, J=4.5, 1.6 Hz, 1H), 8.47 (s, 1H),8.10 (d, J=6.8 Hz, 1H), 7.56-7.45 (m, 4H), 7.45-7.40 (m, 1H), 7.24 (s,1H), 7.00 (dd, J=6.7, 4.5 Hz, 1H), 5.16 (p, J=6.9 Hz, 1H), 4.11 (s, 3H),1.38 (d, J=6.9 Hz, 3H); LCMS calculated for C₂₃H₂₁ClN₇O (M+H)⁺:m/z=446.1; found: 446.2. LCMS calculated for C₂₃H₂₁ClN₇O (M+H)⁺:m/z=446.1; found: 446.2.

Examples 17 & 18.2-amino-N-(1-(4-chloro-1-((1-methyl-1H-pyrazol-3-yl)methyl)-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate &2-amino-N-(1-(4-chloro-2-((1-methyl-1H-pyrazol-3-yl)methyl)-7-phenyl-2H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

These compounds were synthesized according to the procedure describedfor Example 15, utilizing 3-(chloromethyl)-1-methyl-1H-pyrazole (fromMaybridge) instead of methyl iodide. The residue was dissolved in MeOHand purified by preparative HPLC (C-18 column eluting with awater:acetonitrile gradient [36.4-56.4% acetonitrile] buffered at pH 2with 0.1% trifluoroacetic acid). The title compounds were separable andeach was obtained as a white solid. Peak 1 (Example 18): Retentiontime=5.4 min. ¹H NMR (500 MHz, DMSO-d6) δ 8.89 (dd, J=6.7, 1.6 Hz, 1H),8.53 (dd, J=4.5, 1.6 Hz, 1H), 8.42 (s, 1H), 8.07 (d, J=6.7 Hz, 1H), 7.69(s, 1H), 7.54-7.45 (m, 4H), 7.45-7.40 (m, 2H), 7.22 (s, 1H), 6.98 (dd,J=6.7, 4.5 Hz, 1H), 5.42 (s, 2H), 5.13 (p, J=6.9 Hz, 1H), 3.76 (s, 3H),1.36 (d, J=6.9 Hz, 3H). LCMS calculated for C₂₇H₂₅ClN₉O (M+H)⁺:m/z=526.2; found: 526.2. LCMS calculated for C₂₇H₂₅ClN₉O (M+H)⁺:m/z=526.2; found: 526.2. Peak 2 (Example 17): Retention time=6.2 min.LCMS calculated for C₂₇H₂₅ClN₉O (M+H)⁺: m/z=526.2; found: 526.2.

Example 19.2-amino-N-(1-(4-chloro-1-(2-morpholinoethyl)-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

This compound was synthesized according to the procedure described forExample 15, utilizing 4-(2-bromoethyl)morpholine instead of methyliodide. The residue was dissolved in MeOH and purified by preparativeHPLC (C-18 column eluting with a water: acetonitrile gradient bufferedat pH 10 with 0.1% ammonium hydroxide) to give the title compound as awhite solid. ¹H NMR (600 MHz, DMSO-d6) δ 8.92 (dd, J=6.7, 1.6 Hz, 1H),8.57 (dd, J=4.5, 1.6 Hz, 1H), 8.17 (s, 1H), 8.12 (d, J=6.6 Hz, 1H),7.67-7.63 (m, 1H), 7.63-7.59 (m, 1H), 7.59-7.53 (m, 2H), 7.49-7.46 (m,1H), 7.32 (s, 1H), 7.01 (dd, J=6.7, 4.5 Hz, 1H), 6.41 (s, 2H), 4.85 (p,J=6.8 Hz, 1H), 3.81-3.64 (m, 2H), 3.47-3.39 (m, 4H), 2.41-2.32 (m, 2H),2.13-2.04 (m, 4H), 1.35 (d, J=7.0 Hz, 3H); LCMS calculated forC₂₈H₃₀ClN₈O₂ (M+H)⁺: m/z=545.2; found: 545.2.

Example 20.2-amino-N-(1-(4-chloro-2-(2-morpholino-2-oxoethyl)-7-phenyl-2H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

This compound was synthesized according to the procedure described forExample 15, utilizing 2-chloro-1-morpholinoethanone instead of methyliodide. The residue was dissolved in MeOH and purified by preparativeHPLC (C-18 column eluting with a water:acetonitrile gradient buffered atpH 10 with 0.1% ammonium hydroxide) to give the title compound as awhite solid. ¹H NMR (500 MHz, DMSO-d6) δ 8.89 (dd, J=6.7, 1.6 Hz, 1H),8.55 (dd, J=4.5, 1.6 Hz, 1H), 8.39 (s, 1H), 8.09 (d, J=6.7 Hz, 1H),7.55-7.43 (m, 4H), 7.43-7.36 (m, 1H), 7.24 (s, 1H), 6.98 (dd, J=6.7, 4.5Hz, 1H), 6.39 (s, 2H), 5.45 (s, 2H), 5.12 (p, J=6.9 Hz, 1H), 3.61-3.57(m, 2H), 3.57-3.53 (m, 2H), 3.50-3.46 (m, 2H), 3.43-3.39 (m, 2H), 1.38(d, J=6.9 Hz, 3H); LCMS calculated for C₂₈H₂₈ClN₈O₃ (M+H)⁺: m/z=559.2;found: 559.2.

Example 21 & 22.2-amino-N-(1-(2-(2-aminoethyl)-4-chloro-7-phenyl-2H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate &2-amino-N-(1-(1-(2-aminoethyl)-4-chloro-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. teat-butyl3-(1-(4-chloro-2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-7-phenyl-2H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate& tert-butyl3-(1-(4-chloro-1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate

To a solution of tert-butyl3-(1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate(30 mg, 0.06 mmol, from Example 14, Step 6) in DMF (0.5 mL) was addedpotassium carbonate (23 mg, 0.17 mmol), followed byN-(2-bromoethyl)phthalimide (43 mg, 0.17 mmol) and the reaction mixturewas heated to 80° C. overnight. After cooling to room temperature, thereaction mixture was diluted with EtOAc (10 mL) and washed with water (5mL). The organic layer was dried over MgSO₄, filtered, and concentrated.The title compounds, which were obtained in ˜1:1 ratio, were usedwithout purification (theoretical yield assumed). Peak 1: LCMScalculated for C₃₇H₃₃ClN₈O₅ (M+H)⁺: m/z=705.2; found: 705.2. Peak 2:LCMS calculated for C₃₇H₃₃ClN₈O₅ (M+H)⁺: m/z=705.2; found: 705.2.

Step 2.2-amino-N-(1-(4-chloro-2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-7-phenyl-2H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide&2-amino-N-(1-(4-chloro-1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The mixture of products from the previous step (42 mg, 0.060 mmol,˜1.5:1 mixture with the N1 substituted isomer) was dissolved in CH₂Cl₂(2 mL) and trifluoroacetic acid (0.5 mL, 6 mmol) was added at roomtemperature. After 0.5 h, the volatiles were removed in vacuo and theresidue was used without purification (theoretical yield assumed). Peak1: LCMS calculated for C₃₂H₂₆ClN₈O₃ (M+H)⁺: m/z=605.2; found: 605.2.Peak 2: LCMS calculated for C₃₂H₂₆ClN₈O₃ (M+H)⁺: m/z=605.2; found:605.2.

Step 3.2-amino-N-(1-(2-(2-aminoethyl)-4-chloro-7-phenyl-2H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate &2-amino-N-(1-(1-(2-aminoethyl)-4-chloro-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The mixture of products from the previous step (36 mg, 0.06 mmol) wastaken up in MeOH (2 mL) and treated with hydrazine (90 μL, 3 mmol) atroom temperature. After 2 h, the volatiles were evaporated and theresidue was partitioned between water (10 mL) and EtOAc (10 mL). Thelayers were separated, and the organic layer was dried over MgSO₄,filtered, and concentrated. The residue was dissolved in MeOH andpurified by preparative HPLC (C-18 column eluting with a water:acetonitrile gradient [23-43% acetonitrile] buffered at pH 2 with 0.1%trifluoroacetic acid). The title compounds were separable, and each wasobtained as a white solid. Peak 1 (Example 21): Retention time=4.43.LCMS calculated for C₂₄H₂₄ClN₈O (M+H)⁺: m/z=475.2; found: 475.2. Peak 2(Example 22): Retention time=4.67. LCMS calculated for C₂₄H₂₄ClN₈O(M+H)⁺: m/z=475.2; found: 475.2.

Example 23.2-amino-N-(1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. 1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethanone

To a solution of 1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethanone (39 mg,0.14 mmol, from Example 14, Step 4) in DMF (2 mL) was addedN-bromosuccinimide (31 mg, 0.17 mmol) at room temperature. Afterstirring for 2 h, the reaction mixture was quenched with saturatedNaHCO₃ (5 mL) and extracted with EtOAc (10 mL). The layers wereseparated, and the organic layer was dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography on silicagel (0-35% EtOAc/hexanes) to afford the title compound as an orangesolid (47 mg, 93%). LCMS calculated for C₁₅H₁₁BrClN₂O (M+H)⁺: m/z=349.0;found: 348.9.

Step 2. 1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethanamine

To a solution of 1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethanone(30.0 mg, 0.0858 mmol) in ammonia (2M/EtOH, 2 mL) was added titaniumtetraisopropoxide (51 μL, 0.17 mmol) and the reaction mixture was heatedat 60° C. overnight. The resulting solution was cooled to roomtemperature, then 0° C., and sodium borohydride (9.7 mg, 0.26 mmol) wasadded. After stirring for 0.5 h, the reaction mixture was quenched with1M NH₄OH, filtered, and the filtrate was washed with EtOAc (20 mL). Theorganic layer was washed with water (10 mL) and brine (10 mL), driedover MgSO₄, filtered, and concentrated. The product was used withoutpurification (theoretical yield assumed). LCMS calculated forC₁₅H₁₁BrClN₂(M−NH₂)⁺: m/z=333.0; found: 333.0.

Step 3. tert-butyl3-(1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate

This compound was synthesized according to the procedure described inExample 1, Step 6, starting from1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethanamine (30 mg, 0.086mmol). The product was used without purification (theoretical yieldassumed). LCMS calculated for C₂₇H₂₅BrClN₇O₃(M+H)⁺: m/z=610.1; found:610.1.

Step 4.2-amino-N-(1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The deprotection was performed as described in Example 1, Step 7,starting from tert-butyl3-(1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate(52 mg, 0.086 mmol). The residue was dissolved in MeOH and purified bypreparative HPLC (C-18 column eluting with a water:acetonitrile gradientbuffered at pH 2 with 0.1% trifluoroacetic acid) to give the titlecompound as a white solid. LCMS calculated for C₂₂H₁₈BrClN₇O (M+H)⁺:m/z=510.0; found: 510.0.

Example 24.2-amino-N-(1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. 1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethanone

To a solution of 1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethanone(30.0 mg, 0.0858 mmol, from Example 23, Step 1) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (6.3 mg,0.0086 mmol) in dioxane (1 mL) was added 1.0 M dimethylzinc in heptane(90.1 μL, 0.0901 mmol) dropwise at room temperature, and the reactionmixture was heated to reflux for 2 h. LCMS indicated 50% conversion soan additional 0.5 equiv. dimethylzinc was added and heating wascontinued for an additional 1 h. The reaction mixture was filtered andthe volatiles were evaporated in vacuo. The residue was purified byflash chromatography on silica gel (0-35% EtOAc/hexanes) to afford thetitle compound as a colorless oil (7 mg, 29%). LCMS calculated forC₁₆H₁₄ClN₂O (M+H)⁺: m/z=285.1; found: 285.1.

Step 2. 1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethanamine

This compound was synthesized according to the procedure described inExample 23, Step 2, starting from1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethanone (7 mg, 0.024mmol). The product was used without purification (theoretical yieldassumed). LCMS calculated for C₁₆H₁₄ClN₂ (M−NH₂)⁺: m/z=269.1; found:269.0.

Step 3. tert-butyl3-(1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate

This compound was synthesized according to the procedure described inExample 1, Step 6, starting from1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethanamine (7 mg, 0.024mmol). The product was used without purification (theoretical yieldassumed). LCMS calculated for C281429ClN₇O₃ (M+H)⁺: m/z=546.2; found:546.2.

Step 4.2-amino-N-(1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The deprotection was performed as described in Example 1, Step 7,starting from tert-butyl3-(1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate(13 mg, 0.024 mmol). The residue was dissolved in MeOH and purified bypreparative HPLC (C-18 column eluting with a water:acetonitrile gradientbuffered at pH 2 with 0.1% trifluoroacetic acid) to give the titlecompound as a white solid. LCMS calculated for C₂₃H₂₁ClN₇O (M+H)⁺:m/z=446.1; found: 446.1.

Example 25.2-amino-N-(1-(3,4-dimethyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. 1-(3,4-dimethyl-7-phenyl-1H-indazol-6-yl)ethanone

To a solution of 1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethanone(20.0 mg, 0.0857 mmol, from Example 23, Step 1) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (4.2 mg,0.0057 mmol) in dioxane (1 mL) was added 1.0 M dimethylzinc in heptane(110 μL, 0.11 mmol) dropwise at room temperature, and the reactionmixture was heated to reflux for 4 h. The reaction mixture was filteredand the volatiles were evaporated in vacuo. The residue was purified byflash chromatography on silica gel (O-35% EtOAc/hexanes) to afford thetitle compound as a colorless oil (10 mg, 67%). LCMS calculated forC₁₇H₁₇N₂O (M+H)⁺: m/z=265.1; found: 265.1.

Steps 2-4.2-amino-N-(1-(3,4-dimethyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

This compound was synthesized starting from1-(3,4-dimethyl-7-phenyl-1H-indazol-6-yl)ethanone (10 mg, 0.038 mmol)following the procedure described for Example 24, steps 2-4. The residuewas dissolved in MeOH and purified by preparative HPLC (C-18 columneluting with a water: acetonitrile gradient buffered at pH 2 with 0.1%trifluoroacetic acid) to give the title compound as a white solid. LCMScalculated for C₂₄H₂₄N₇O (M+H)⁺: m/z=426.2; found: 426.3.

Example 26.2-Amino-N-{1-[8-chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (mixture of diastereomers prepared)

Step 1. Methyl 2,5-dichloronicotinate

A solution of 2,5-dichloronicotinic acid (20.0 g, 104 mmol, OChem) inDCM (520 mL) was treated with oxalyl chloride (26. mL, 310 mmol)followed by DMF (0.015 mL, 0.19 mmol). The reaction was stirredovernight. The reaction mixture was then concentrated in vacuo. The acidchloride was diluted with DCM (200 mL), cooled to 0° C. and treated withMeOH (110 mL). After stirring for 30 minutes, solvents were removed invacuo. The crude residue was dissolved in DCM and washed sequentiallywith saturated NaHCO₃ solution, water, and saturated NaCl solution. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated toafford a white crystalline solid that was used without furtherpurification. Yield: 18.8 g, 90%. LCMS calculated for C₇H₆Cl₂NO₂(M+H)⁺:m/z=206.0; found: 206.0.

Step 2. Methyl 2,5-dichloronicotinate 1-oxide

H₂O₂ (30% in water, 19.6 mL, 640 mmol) was added to methyl2,5-dichloronicotinate (19.4 g, 94.2 mmol, prepared as in Step 1) in TFA(118 mL). The reaction mixture was heated to 70° C. for 1 hour. Solventwas removed in vacuo and the product was purified by flashchromatography, eluting with a gradient from 0-100% ethyl acetate inhexanes to afford a white solid. Yield: 17.4 g, 83%. LCMS calculated forC₇H₆Cl₂NO₃(M+H)⁺: m/z=222.0; found: 222.0.

Step 3. Methyl 2,5-dichloro-6-cyanonicotinate

Triethylamine (16.6 mL, 119 mmol) and trimethylsilyl cyanide (25.9 mL,194 mmol) were added to a solution of methyl 2,5-dichloronicotinate1-oxide (17.4 g, 78.4 mmol, from Step 2) in acetonitrile (150 mL). Thereaction mixture was heated to 70° C. for 20 minutes. Upon cooling toroom temperature, the reaction mixture was diluted with EtOAc, and thesolution was quenched by slow addition to a cold solution of aqueousK₂CO₃ (500 mL). The resulting aqueous mixture was extracted with DCM.The combined organic extracts were washed with water, followed by brine,dried over Na₂SO₄, filtered, and concentrated. The product was purifiedby flash chromatography, eluting with a gradient from 0-50%EtOAc/hexanes. Yield: 16.3 g, 90%. LCMS calculated forC₈H₄Cl₂N₂O₂(M+H)⁺: m/z=231.0; found: 231.0.

Step 4. Methyl 5-chloro-6-cyano-2-(3-fluorophenyl)nicotinate

A degassed mixture of methyl 2,5-dichloro-6-cyanonicotinate (5.0 g, 22mmol, from Step 3), (3-fluorophenyl)boronic acid (3.33 g, 23.8 mmol,Aldrich), bis(triphenylphosphine)palladium(II) chloride (1.05 g, 1.50mmol), K₂CO₃ (6.52 g, 47.2 mmol) in water (39.0 mL), and 1,4-dioxane(101 mL) was heated at 80° C. for 1 hour. The reaction mixture wasdiluted with EtOAc and water. The aqueous layer was separated andextracted with additional EtOAc. The combined organic extracts werewashed with water, followed by brine, dried over Na₂SO₄, filtered, andconcentrated. The product was purified by flash chromatography, elutingwith a gradient from 0-30% EtOAc in hexanes to afford the product as alight yellow solid. Yield: 5.5 g, 87%. LCMS calculated for C₁₄H₉ClFN₂O₂(M+H)⁺: m/z=291.0; found: 291.0.

Step 5. Methyl 6-(aminomethyl)-5-chloro-2-(3-fluorophenyl)nicotinateacetate salt

A solution of methyl 5-chloro-6-cyano-2-(3-fluorophenyl)nicotinate (5.5g, 19 mmol, from Step 4) in acetic acid (55 mL) was degassed and thenstirred under 1 atm of H2 over Pd on C (5%, 2.4 g, 1.1 mmol) for 3hours. The mixture was filtered through Celite® and solvent was removedin vacuo to afford a crystalline solid. The solid was slurried in waterand filtered, and the solids were washed with water to give the desiredcompound as the acetate salt, contaminated with a small amount of thedes-chloro byproduct, the bulk of which remained in the filtrate. Yield:1.9 g, 26%. LCMS calculated for C₁₄H₁₃C1FN202(M+H)⁺: m/z=295.1; found:295.0.

Step 6. Methyl6-[(acetylamino)methyl]-5-chloro-2-(3-fluorophenyl)nicotinate

To methyl 6-(aminomethyl)-5-chloro-2-(3-fluorophenyl)nicotinate acetate(0.90 g, 2.5 mmol, from Step 5) and N,N-diisopropylethylamine (0.88 mL,5.1 mmol) in NN-dimethylformamide (7.4 mL) was added acetic anhydride(0.26 mL, 2.8 mmol). After 30 minutes, the mixture was quenched withsaturated NaHCO₃ solution and diluted with water. The aqueous mixturewas extracted with

EtOAc. The combined organic extracts were washed sequentially with waterand brine, dried over Na₂SO4, and concentrated to give product that wasused without further purification. Yield: 0.85 g, 100%. LCMS calculatedfor C₁₆H₁₅ClFN₂O₃(M+H)⁺: m/z=337.1; found: 337.1.

Step 7. Methyl8-chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridine-6-carboxylate

Methyl 6-Racetylamino)methyl1-5-chloro-2-(3-fluorophenyl)nicotinate(0.85 g, 2.5 mmol, from Step 6) in POCl₃ (10 mL, 110 mmol) was heated to90° C. for 35 minutes. The mixture was then evaporated to remove POCl₃.The product was purified by flash chromatography, eluting with agradient from 0-100% EtOAc (containing 1% MeOH and 1%NH4OH) in hexanes.Yield: 0.70 g, 78%. LCMS calculated for C₁₆H₁₃ClFN₂O₂(M+H)⁺: m/z=319.1;found: 319.1.

Step 8.8—Chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridine-6-carboxylicacid

Methyl8-chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridine-6-carboxylate(230 mg, 0.72 mmol, from Step 7) in MeOH (5 mL) was treated with 3.0 MNaOH in water (0.96 mL, 2.9 mmol) and stirred for 5 hours. The mixturewas acidified with acetic acid and the solvents were removed in vacuo.Trituration with water gave the desired compound as a light yellowsolid, which was isolated by filtration and air dried. Yield: 0.20 g,91%. LCMS calculated for C₁₅H₁₁ClFN₂O₂ (M+H)⁺: m/z=305.0; found: 305.0.

Step 9.8—Chloro-5-(3-fluorophenyl)-N-methoxy-N3-dimethylimidazo[1,5-a]pyridine-6-carboxamide

To a suspension of8-chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridine-6-carboxylicacid (0.20 g, 0.66 mmol, from Step 8) in DMF (1.8 mL) was addedN,N-diisopropylethylamine (0.572 mL, 3.28 mmol), NO-dimethylhydroxylamine hydrochloride (0.192 g, 1.97 mmol), 0.6 M1-hydroxy-7-azabenzotriazole in DMF (0.219 mL, 0.131 mmol), andN-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.189 g,0.984 mmol). The precipitate slowly dissolved, and the resultingsolution was stirred overnight. Saturated NaHCO3 was added, and themixture was extracted with three portions of EtOAc. The combined organicextracts were washed sequentially with water and brine, dried overNa₂SO₄, filtered and concentrated. The product was purified by flashchromatography, eluting with a gradient of 0-80% EtOAc in hexanes toafford product as a yellow solid. Yield: 0.18 g, 79%. LCMS calculatedfor C₁₇H₁₆ClFN₃O₂(M+H)⁺: m/z=348.1; found: 348.0.

Step 10.1-[8—Chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethanone

3.0 M Methylmagnesium bromide in THF (0.78 mL, 2.3 mmol) was addeddropwise to a 0° C. solution of8-chloro-5-(3-fluorophenyl)-N-methoxy-N,3-dimethylimidazo[1,5-a]pyridine-6-carboxamide(0.18 g, 0.52 mmol, from Step 9) in anhydrous THF (5.0 mL, 62 mmol)under N2. The solution was stirred at 0° C. for 1.5 hours. The reactionwas quenched at 0° C. by the addition of 1.0 M HCl in water (2.6 mL, 2.6mmol). The mixture was then made basic by the addition of saturatedNaHCO₃ solution. The mixture was extracted with EtOAc (75 mL). Theorganic extract was washed with water, followed by brine, dried overNa₂SO₄, filtered, and concentrated to afford the product as a yellowsolid, which was used without further purification. Yield: 0.14 g, 89%.LCMS calculated for Cl₆H₁₃ClFN₂O (M+H)⁺: m/z=303.1; found: 303.0.

Step 11.1-[8-Chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethanamine(mixture of diastereomers prepared)

A mixture of1-[8-chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethanone(0.14 g, 0.46 mmol, from Step 10) and ammonium acetate (0.356 g, 4.62mmol) in methanol (5.2 mL) was heated at 65° C. for 1 hour. Sodiumcyanoborohydride (87 mg, 1.4 mmol) was then added and heating wascontinued for 1 hour. Additional ammonium acetate (0.356 g, 4.62 mmol)and sodium cyanoborohydride (0.087 g, 1.4 mmol) were added and heatingwas continued for a total of 22 hours. Upon cooling to room temperature,saturated NaHCO3 solution was added and the mixture was extracted withtwo portions of EtOAc. The combined organic extracts were dried overNa₂SO₄, filtered, and concentrated. To remove further impurities, theresidue was dissolved in 1N HCl and washed with EtOAc. The aqueous layerwas made basic again by the addition of NaHCO₃ solution, and wasextracted with EtOAc. The extract was again dried over Na₂SO₄, filtered,and concentrated. The product was purified by preparative HPLC-MS (pH10). Yield: 61 mg, 43%. LCMS calculated for C₁₆H₁₆ClFN₃(M+H)⁺:m/z=304.1; found: 304.1.

Step 12.2-Amino-N-{1-[8-chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (mixture of diastereomers prepared)

1-[8-Chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethanamine(20. mg, 0.066 mmol, from Step 11) in DMF (0.45 mL) was added to amixture of2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (18 mg, 0.066 mmol, J&W Pharmlab),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (30. mg, 0.079 mmol) and N,N-diisopropylethylamine(23 μL, 0.13 mmol) in DMF (0.4 mL). After stirring for 40 minutes, waterwas added and the precipitated product was isolated by filtration andair dried. The white solid so obtained was stirred with TFA (0.2 mL) inDCM (0.5 mL) for 30 minutes. Solvent was removed in vacuo and theresidue was reconstituted in acetonitrile and purified by preparativeHPLC-MS (pH 2). Yield: 20 mg. ¹H NMR (400 MHz, DMSO-d₆, mixture ofdiastereomers) δ 8.95-8.88 (m, 2H), 8.60-8.50 (m, 2H), 8.09-7.95 (m,2H), 7.87 (s, 2H), 7.76-7.59 (m, 4H), 7.59-7.42 (m, 4H), 7.35 (s, 1H),7.34 (s, 1H), 7.05-6.99 (m, 2H), 6.43 (br s, 4H), 4.68-4.38 (m, 2H),1.88 (s, 3H), 1.88 (s, 3H), 1.41 (d, J=6.9 Hz, 3H), 1.40 (d, J=6.9 Hz,3H); LCMS calculated for C₂₃H₂₀ClFN₇O (M+H)⁺: m/z=464.1; found: 464.1.

Example 27.2-Amino-N-(1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (single enantiomer prepared)

Step 1. Methyl 5-chloro-6-cyano-2-phenylnicotinate

The title compound was prepared as in Example 26, Step 4, using2,5-dichloro-6-cyanonicotinate (5.80 g, 25.1 mmol, prepared as inExample 26, Step 3) and phenylboronic acid (3.67 g, 30.1 mmol, Aldrich).Yield: 6.33 g, 93%. NMR (400 MHz, DMSO-d₆) δ 8.63 (s, 1H), 7.57-7.48 (m,5H), 3.74 (s, 3H); LCMS calculated for C₁₄H₂₀ClN₂O₂(M+H)⁺: m/z=273.0;found: 273.0.

Step 2. Methyl 6-(aminomethyl)-5-chloro-2-phenylnicotinate

To methyl 5-chloro-6-cyano-2-phenylnicotinate (1.01 g, 3.70 mmol, fromStep 1) in methanol (50. mL) was added Raney Ni (1.0 mL of Raney® Nickelsuspension in water). The mixture was degassed and stirred under H₂ (1atm) for 2 hours. The mixture was filtered through Celite®, and theCelite® was washed with methanol. Solvent was removed from the filtrateto afford product, which was used without further purification in Step3. Yield: 1.0 g, 97%. LCMS calculated for C₁₄H₁₄ClN₂O₂(M+H)⁺: m/z=277.1;found: 277.1.

Step 3. Methyl 5-chloro-6-[(formylamino)methyl]-2-phenylnicotinate

Formic acid (6.7 mL, 180 mmol) and acetic anhydride (1.7 mL, 18 mmol)were combined and stirred for 40 minutes, then the mixture was addeddropwise into a 0° C. solution of methyl6-(aminomethyl)-5-chloro-2-phenylnicotinate (1.0 g, 3.6 mmol, from Step2) in DCM (20 mL). After stirring for 50 minutes at 0° C., the solutionwas warmed to room temperature and stirred overnight. Solvent wasremoved in vacuo to afford 1.34 g of crude product which was usedwithout further purification in Step 4. LCMS calculated forC₁₅H₁₄ClN₂O₃(M+H)⁺: m/z=305.1; found: 305.0.

Step 4. Methyl 8-chloro-5-phenylimidazo[1,5-a]pyridine-6-carboxylate

Methyl 5-chloro-6-[(formylamino)methyl]-2-phenylnicotinate (1.13 g, 3.71mmol, from Step 3) in POCl₃ (5.5 mL, 59 mmol) was heated to 75° C. for35 minutes. Upon cooling to room temperature, the mixture was pouredslowly onto crushed ice, and the ice-cold mixture was neutralized by theaddition of solid Na₂CO₃. The aqueous mixture was extracted with DCM.The organic phase was dried over Na₂SO₄, filtered, and concentrated. Theproduct was purified by flash chromatography, eluting with a gradientfrom 0-30% EtOAc in hexanes. Yield: 0.76 g, 71%. ¹H NMR (400 MHz,DMSO-d₆) δ 7.77 (s, 1H), 7.65 (s, 1H), 7.63-7.57 (m, 3H), 7.56-7.49 (m,2H), 7.41 (s, 1H), 3.57 (s, 3H); LCMS calculated forC151⁻112C1N202(M+H)^(±): m/z=287.1; found: 287.1.

Step 5. 8—Chloro-5-phenylimidazo[1,5-a]pyridine-6-carboxylic acid

The title compounds was prepared as in Example 26, Step 8, using methyl8-chloro-5-phenylimidazo[1,5-a]pyridine-6-carboxylate (0.75 g, 2.6 mmol,from Step 4). Yield: 0.70 g, 98%. LCMS calculated forC₁₄H₁₀ClN₂O₂(M+H)⁺: m/z=273.0; found: 273.0.

Step 6.8—Chloro-N-methoxy-N-methyl-5-phenylimidazo[1,5-a]pyridine-6-carboxamide

The title compound was prepared as in Example 26, Step 9, using8-chloro-5-phenylimidazo[1,5-a]pyridine-6-carboxylic acid (0.70 g, 2.6mmol, from Step 5). Yield: 0.62 g, 76%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.02(s, 1H), 7.64 (s, 1H), 7.60 (s, 5H), 7.22 (s, 1H), 3.49 (br s, 3H), 3.00(br s, 3H); LCMS calculated for C₁₆H₁₅ClN₃O₂(M+H)⁺: m/z=316.1; found:316.0.

Step 7. 1-(8-Chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanone

The title compound was prepared from8-chloro-N-methoxy-N-methyl-5-phenylimidazo[1,5-a]pyridine-6-carboxamide(0.62 g, 2.0 mmol, from Step 6) by the procedure of Example 26, Step 10.The product was used without further purification in Step 8. ¹H NMR (400MHz, CDCl₃) δ 8.03 (s, 1H), 7.75 (s, 1H), 7.71-7.61 (m, 3H), 7.53-7.42(m, 2H), 7.37 (s, 1H), 1.96 (s, 3H); LCMS calculated for C₁₅H₁₂ClN₂O(M+H)⁺: m/z=271.1; found: 271.1.

Step 8. 1-(8-Chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanamine(scalemic mixture prepared)

A solution of 1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-ypethanone(0.28 g, 0.83 mmol, from Step 7) and (R)-2-methylpropane-2-sulfinamide(0.22 g, 1.8 mmol, CombiBlocks) in THF (3.0 mL) was treated withtitanium(IV) ethoxide (380 μL, 1.8 mmol, Strem), and was heated to 70°C. in a sealed reaction vessel overnight. The reaction mixture wascooled to −44° C. and 1.0 M L-Selectride® in THF (2.9 mL, 2.9 mmol) wasadded dropwise. The reaction mixture was warmed to room temperature over1 hour. The reaction mixture was then cooled to 0° C. and was quenchedby the addition of MeOH (0.50 mL). Upon warming to room temperature, themixture was diluted with EtOAc (25 mL) and brine (0.20 mL) and wasstirred for 5 minutes. The slurry was filtered through Celite®, and thefilter cake was washed with EtOAc. The filtrate was concentrated to givea residue. LCMS indicated a mixture of diastereomers, a major and aminor isomer, which were not separated. The residue was dissolved inmethanol (7.5 mL) and treated with 4.0 N HCl in dioxane (6.2 mL, 25mmol) for 1 hour. Solvent was removed in vacuo and the residue wasreconstituted in MeOH and purified via preparative HPLC-MS (pH=2). Thefractions containing product were evaporated to remove most of theacetonitrile. The aqueous mixture was made basic (pH 10) by the additionof sodium carbonate. The basic aqueous mixture was saturated with NaCland extracted twice with DCM. The combined organic extracts were driedover Na₂SO₄, filtered, and concentrated to afford product as a whitesolid. Yield: 91 mg, 40%. ¹H NMR (400 MHz, DMSO-d₆) δ 7.69-7.56 (m, 4H),7.54 (s, 1H), 7.52-7.47 (m, 2H), 7.38 (s, 1H), 3.65 (q, J=6.5 Hz, 1H),1.90 (br s, 2H), 1.16 (d, J=6.6 Hz, 3H); LCMS calculated forC₁₅H₁₅ClN₃(M+H)⁺: m/z=272.1; found: 272.1.

Step 9. teat-Butyl[3-({[1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate(single enantiomer isolated)

A solution of 1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanamine(84 mg, 0.31 mmol, from Step 8) in DMF (2.1 mL) was added to a mixtureof 2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (95 mg, 0.34 mmol, J&W Pharmlab),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (130 mg, 0.34 mmol) and N,N-diisopropylethylamine(110 μL, 0.62 mmol) in DMF (2 mL). After 30 minutes, saturated NaHCO₃was added. Dilution with water resulted in a precipitate, which wasisolated by filtration. The solid product was washed with water, and wasair dried. The solid was then dissolved in DCM, and the solution wasfiltered to remove insoluble impurities. The filtrate was concentratedto afford the product as a light yellow solid. Yield: 0.15 g, 91%. LCMScalculated for C₂₇H₂₇ClN₇O₃ (M+H)⁺: m/z=532.2; found: 532.2. Thescalemic mixture was separated by HPLC (Phenomenex Lux Cellulose C-1, 5μm, 21.2×250 mm, 9 mg/900 μL loading, eluting with 20% EtOH in hexanesat 18 mL/min over 13 min). This provided Enantiomer 1 (first to elute,major component, retention time 8.3 min, Yield: 76 mg), and Enantiomer 2(second to elute, minor component, retention time 10.9 min, Yield: 10mg).

Step 10.2-Amino-N-[1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (single enantiomer)

tert-Butyl[3-({[1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate(76 mg, 0.14 mmol, Enantiomer 1 from Step 9) was stirred with TFA (0.5mL) in DCM (2.0 mL) for 30 minutes. The solvents were removed in vacuo,and the product was reconstituted in acetonitrile and purified bypreparative HPLC-MS (pH 2). Yield: 69 mg, 83%, (1.4×TFA salt). ¹H NMR(500 MHz, DMSO-d₆) δ 8.90 (dd, J=6.7, 1.6 Hz, 1H), 8.54 (dd, J=4.5, 1.6Hz, 1H), 8.02 (d, J=6.4 Hz, 1H), 7.96 (s, 1H), 7.84-7.78 (m, 1H), 7.76(s, 1H), 7.72-7.66 (m, 1H), 7.66-7.60 (m, 2H), 7.60-7.54 (m, 1H), 7.35(s, 1H), 6.99 (dd, J=6.7, 4.5 Hz, 1H), 4.75 (p, J=7.0 Hz, 1H), 1.41 (d,J=7.0 Hz, 3H); LCMS calculated for C₂₂H₁₉ClN₇O (M+H)⁺: m/z=432.1; found:432.1.

Example 28.2-Amino-N-[1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (single enantiomer)

tert-Butyl[3-({[1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate(10 mg, 0.019 mmol, Enantiomer 2 from Example 27, Step 9) was stirredwith TFA (0.2 mL) in DCM (1.0 mL) for 30 minutes. The solvents wereremoved in vacuo, and the product was reconstituted in acetonitrile andpurified by preparative HPLC-MS (pH=2). Yield: 4.9 mg, 45%. ¹H NMR (400MHz, DMSO-d₆) δ 8.92 (dd, J=6.7, 1.5 Hz, 1H), 8.56 (dd, J=4.5, 1.5 Hz,1H), 8.04 (d, J=6.4 Hz, 1H), 7.87-7.77 (m, 2H), 7.77-7.52 (m, 5H), 7.32(s, 1H), 7.01 (dd, J=6.7, 4.5 Hz, 1H), 4.76 (p, J=6.8 Hz, 1H), 1.43 (d,J=7.0 Hz, 3H); LCMS calculated for C₂₂H₁₉ClN₇O (M+H)⁺: m/z=432.1; found:432.1.

Example 29.2-Amino-N-{1-[5-(3-fluorophenyl)-3,8-dimethylimidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (mixture of diastereomers prepared)

Step 1.1-[5-(3-Fluorophenyl)-3,8-dimethylimidazo[1,5-a]pyridin-6-yl]ethanone

A solution of1-[8-chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethanone(0.046 g, 0.15 mmol, from Example 26, Step 10) and 1.0 M dimethylzinc inheptane (0.30 mL, 0.30 mmol) in 1,4-dioxane (2 mL) was degassed and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.011 g,0.015 mmol) was added. The reaction mixture was heated to 100° C. for 2hours in a sealed reaction vial. The reaction mixture was then pouredinto saturated NaHCO₃ and the aqueous mixture was extracted with threeportions of EtOAc. The combined organic extracts were washed with brine,dried over Na₂SO₄, filtered, and concentrated. The product was purifiedby flash chromatography, eluting with a gradient from 0-100%EtOAc/hexanes. LCMS calculated for C₁₇H₁₆FNO₂(M+H)⁺: m/z=283.1; found:283.1.

Step 2.1-[5-(3-Fluorophenyl)-3,8-dimethylimidazo[1,5-a]pyridin-6-yl]ethanamine(mixture of diastereomers prepared)

Titanium tetraisopropoxide (0.052 mL, 0.18 mmol) was added to a mixtureof 1-[5-(3-fluorophenyl)-3,8-dimethylimidazo[1,5-a]pyridin-6-yl]ethanone(0.025 g, 0.088 mmol, prepared as in Step 1) in 2.0 M ammonia in ethanol(0.22 mL, 0.44 mmol). The reaction was heated to 60° C. for 2 hours. Thereaction mixture was then cooled to 0° C., and NaBH₄ (0.0050 g, 0.13mmol) was added. After 30 minutes, the reaction mixture was quenchedwith water and insoluble material was removed by filtration. The solidswere washed with acetonitrile. The filtrate was concentrated and theproduct was used without further purification in Step 3. LCMS calculatedfor C₁₇H₁₉FN₃(M+H)⁺: m/z=284.1; found: 284.1.

Step 3.2-Amino-N-{1-[5-(3-fluorophenyl)-3,8-dimethylimidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (mixture of diastereomers prepared)

A solution of1-[5-(3-fluorophenyl)-3,8-dimethylimidazo[1,5-a]pyridin-6-yl]ethanamine(0.025 g, 0.088 mmol, as a mixture of diastereomers from Step 2) in DMF(2 mL) was treated with2-[tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(0.039 g, 0.14 mmol, J&W Pharmlab), N,N-diisopropylethylamine (0.046 mL,0.26 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.074 g, 0.19 mmol). After stirring for 2 hours,the reaction mixture was diluted with water and extracted with EtOAc.The combined organic extracts were dried over Na₂SO₄, filtered, andconcentrated. The crude product was deprotected by stirring with TFA (1mL) in DCM (1 mL) for 1 hour. The solvents were removed in vacuo and theresidue was reconstituted in MeCN and purified via preparative HPLC-MS(pH 2). Yield: 8 mg. ¹H NMR (400 MHz, CD₃OD, mixture of diastereomers) δ8.74-8.68 (m, 2H), 8.58-8.53 (m, 2H), 8.00 (s, 2H), 7.77-7.58 (m, 4H),7.50-7.35 (m, 4H), 7.17 (s, 2H), 7.04-6.95 (m, 2H), 4.82-4.69 (m, 2H),2.53 (s, 6H), 2.09 (s, 6H), 1.51 (d, J=6.9 Hz, 3H), 1.50 (d, J=6.9 Hz,3H); LCMS calculated for C₂₄H₂₃FN₇O (M+H)⁺: m/z=444.1; found: 444.1.

Example 30.2-Amino-N-[1-(8-cyano-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt

Step 1. 6-Acetyl-5-phenylimidazo[1,5-a]pyridine-8-carbonitrile

A microwavable vial was charged with1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanone (50. mg, 0.18mmol, from Example 27, Step 7), Zn(CN)₂ (24 mg, 0.20 mmol),tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (11 mg, 0.011mmol), and 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (7.6mg, 0.018 mmol). DMF (3.35 mL) and water (17 μL, 0.92 mmol) were added.The mixture was degassed and the reaction was heated in the microwave to150° C. for 30 minutes. The reaction mixture was poured into saturatedNaHCO₃ and extracted with three portions of EtOAc. The combined organicextracts were washed with water, then brine, dried over Na₂SO₄, filteredand concentrated. The product was purified by flash chromatography,eluting with a gradient from 0-40% EtOAc/hexanes, to afford a yellowsolid. Yield: 37 mg, 77%. LCMS calculated for C₁₆H₁₁N₃O (M+H)⁺:m/z=262.1; found: 262.2.

Step 2. 6-(1-Aminoethyl)-5-phenylimidazo[1,5-a]pyridine-8-carbonitrile(racemic mixture prepared)

6-Acetyl-5-phenylimidazo[1,5-a]pyridine-8-carbonitrile (36 mg, 0.14mmol, from Step 1) was dissolved in MeOH (1.5 mL) and ammonium acetate(106 mg, 1.38 mmol) was added. The resulting mixture was heated at 65°C. for 1 hour. Sodium cyanoborohydride (26 mg, 0.41 mmol) was added andthe solution was heated at 65° C. overnight. Upon cooling to roomtemperature, the reaction was quenched by the addition of water wasadded. The mixture was diluted with acetonitrile and the product waspurified by preparative HPLC-MS (pH 10; eluting with a gradient from19.4-37.4% MeCN in water in 12 minutes), which afforded two peaks withthe desired mass. The desired product was Peak 1, the minor isomer(eluting at a retention time of 7.0 min), which on evaporation, affordeda yellow solid that was used in Step 3. Yield: 2.8 mg, 8%. LCMScalculated for C₁₆H₁₅N₄(M+H)⁺: m/z=263.1; found: 263.1.

Step 3.2-Amino-N-[1-(8-cyano-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

A mixture of2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (3.3 mg, 0.012 mmol),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (4.5 mg, 0.012 mmol) and N,N-diisopropylethylamine(3.7 μL, 0.021 mmol) in DMF (0.20 mL) was stirred for 5 minutes, and6-(1-aminoethyl)-5-phenylimidazo[1,5-a]pyridine-8-carbonitrile (2.8 mg,0.011 mmol, Peak 1 from Step 2) in DMF (0.22 mL) was then added. After30 minutes, the reaction was diluted with saturated NaHCO₃, followed bywater. The aqueous mixture was extracted with EtOAc and the solvent wasremoved in vacuo. The crude product was stirred with TFA (0.10 mL) inDCM (0.50 mL) for 1 hour and the solvents were evaporated. The residuewas dissolved in acetonitrile and purified by preparative HPLC-MS(pH=2). Yield: 2.5 mg.

¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (dd, J=6.7, 1.5 Hz, 1H), 8.56 (dd,J=4.5, 1.6 Hz, 1H), 8.05 (d, J=6.2 Hz, 1H), 7.93 (s, 1H), 7.85 (d, J=7.6Hz, 1H), 7.78-7.57 (m, 6H), 7.01 (dd, J=6.7, 4.5 Hz, 1H), 6.44 (br s,2H), 4.74 (p, J=6.7 Hz, 1H), 1.44 (d, J=7.0 Hz, 3H); LCMS calculated forC₂₃H₁₉N₈O (M+H)⁺: m/z=423.1; found: 423.1.

Examples 31A-31B.2-Amino-N-((1S)-1-(8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (Isomers 1-2, scalemic mixture prepared)

Sp 1. Benzyl 2-methylthiomorpholine-4-carboxylate 1,1-dioxide (singleisomers)

To the suspension of 2-methylthiomorpholine 1,1-dioxide hydrochloride(0.25 g, 1.4 mmol) (racemic mixture, Enamine Building Blocks,EN300-137734) in dichloromethane (4.5 mL) was added triethylamine (0.75mL, 3.5 mmol). The mixture was cooled to 0° C. Benzyl chloroformate(0.29 mL, 2.0 mmol) was added dropwise. White suspension was observed.The reaction mixture was warmed to room temperature and stirred for 2 hbefore the solvent was removed under vacuum. The crude product waspurified by flash column chromatography (0.35 g, 93% yield). Thepurified product was submitted for chiral HPLC purification (PhenomenexLux Amylose 1 column) to afford the two enantio-pure isomers.

Step 2. 2-Methylthiomorpholine 1,1-dioxide (single isomers)

A solution of benzyl 2-methylthiomorpholine-4-carboxylate 1,1-dioxide(0.12 g, 0.42 mmol, peak 2, step 1) in ethyl acetate (2 ml) was degassedwith nitrogen gas for 3 minutes before palladium (10% on carbon, 0.045g, 0.04 mmol) was added. After degassing for another 3 min, the mixturewas put under vacuum and hydrogen (1 atm) was then charged into thereaction vessel. The mixture was stirred at room temperature for 12 h.After filtration through Celite, the resulting solution was concentratedunder vacuum to afford 2-methylthiomorpholine 1,1-dioxide (single isomer1, 0.06 g, 0.402 mmol, 95% yield). Single isomer 2 was synthesizedaccording to the above procedure, using peak 1 from step 1 as thestarting material.

Step 3.1-(8-fluoro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethan-1-one(single isomer)

A solution of 1-(5,8-dichloroimidazo[1,5-a]pyridin-6-yl)ethan-1-one(0.64 g, 2.8 mmol) (Example 130, Step 7), 2-methylthiomorpholine1,1-dioxide (single isomer 1, step 2, 0.54 g, 3.6 mmol) andN,N-diethylpropan-2-amine (1.3 mL, 8.4 mmol) in acetonitrile (9 mL) washeated at 140° C. in a microwave reactor and stirred for 5 h. Aftercooling to room temperature, the solvents were removed under vacuum andthe resulting residue was purified by flash column chromatography(0-100% ethyl acetate in hexane to 0-35% methanol in ethyl acetate) toafford1-(8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethan-1-one(0.9 g, 94% yield) LCMS calculated for C₁₄H₁₇O₃N₃SCl (M+H)⁺: m/z=342.1;found 342.0.

Step 4.(S)—N-((1S)-1-(8-Chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl)-2-methylpropane-2-sulfinamide(single isomer, scalemic mixture)

To a suspension of1-(8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethan-1-one(1.9 g, 5.6 mmol) and (S)-2-methylpropane-2-sulfinamide (6.7 g, 55.6mmol) in cyclopentyl methyl ether (4 mL) was added titaniumtetraisopropoxide (4.9 mL, 16.6 mmol). The reaction mixture was heatedto 100° C. and stirred for 36 h. The reaction mixture was cooled to 0°C. and sodium tetrahydroborate (1.05 g, 27.8 mmol) was added in oneportion. The mixture was warmed to room temperature and stirred for 8 h.The reaction mixture was cooled to 0° C. and was quenched by thedropwise addition of methanol (1 mL). The resulting solution was pouredinto brine. The suspension was filtered through celite. The filtrate wasdiluted with ethyl acetate and the layers were separated. The organiclayer was dried over sodium sulfate, filtered, and concentrated, and theresidue was purified by flash column chromatography to afford thedesired product (1.9 g, 77% yield). LCMS calculated for C₁₈H₂₈O₃N₄S₂Cl(M+H)⁺: m/z=447.1; found 447.2.

Step 5.(1S)-1-[1,8-Dichloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethanaminehydrogen chloride salt (single diasteromer, scalemic mixture)

To the solution of(S)—N-(1-(8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl)-2-methylpropane-2-sulfinamide(1.9 g, 4.2 mmol) in methanol (10 mL) was added hydrogen chloride (4M indioxane, 10 mL) at 0° C. The mixture was warmed to room temperature andstirred for 1 h. Volatiles were removed under vacuum to afford the crudeproduct as a HCl salt, which was used without further purification. LCMScalculated for C₁₄H₂₀ClN₄O₂S (M+H)⁺: m/z=343.1; found 343.1.

Step 6.2-Amino-N-(1-[8-chloro-5-(2-methyl-1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (single diasteromer, scalemic mixture)

N,N-Diethylpropan-2-amine (2.45 ml, 15.8 mmol) was added to2-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (1.32 g, 4.7 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (1.65 g, 4.3 mmol) in N,N-dimethylformamide (8 mL).After stirring for 10 minutes a suspension of(1S)-1-[1,8-dichloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethanaminehydrogen chloride salt (step 5, 1.5 g, 3.9 mmol) inN,N-dimethylformamide (3 mL) was added dropwise. The reaction wasstirred for 1 h at room temperature. The reaction was diluted with water(100 mL) and filtered. The cake was washed with water (10 mL) andair-dried for 2 h. Trifluoroacetic acid (10 mL) was added to a solutionof the crude product in dichoromethane (10 mL). After stirring for 1 hat room temperature, volatiles were removed in vacuo and the product waspurified by preparative LCMS (pH 2) to afford2-amino-N-(1-[8-chloro-5-(2-methyl-1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (Isomer 1, 0.2 g, 8.2% yield). LCMS calculated forIsomer 1: C₂₁H₂₄O₃N₈SCl (M+H)⁺: m/z=503.1; found 503.1. ¹H NMR (600 MHz,DMSO, mixture of scalemic isomers): δ 9.31 (s, 0.6H), 8.94-8.86 (m, 1H),8.82 (s, 0.4H), 8.62-8.48 (m, 1H), 8.16-8.01 (m, 1H), 7.88 (s, 0.6 H),7.73 (s, 0.4 H), 7.26 (m, 1H), 7.06-6.91 (m, 1H), 5.54 (p, J=7.0 Hz, 0.4H), 5.20 (p, J=6.9 Hz, 0.6 H), 3.89-3.77 (m, 0.6 H), 3.77-3.51 (m, 4H),3.50-3.36 (m, 0.4 H), 3.34-3.17 (m, 2H), 1.56 (m, 3H), 1.27 (d, J=6.9Hz, 1H), 1.17 (d, J=6.8 Hz, 2H).

Isomer 2 was synthesized according to steps 3-6, using single isomer 2from step 2 as starting material for step 3. LCMS calculated for Isomer2: C₂₁H₂₄O₃N₈SCl (M+H)⁺: m/z=503.1; found 503.1.

Examples 32-40

The following Examples 32-40 in Table 3 were prepared by the method ofExample 149. NMR data for representative compounds of Table 3 areprovided in Table 3a.

TABLE 3

Ex. No. Name R = LCMS 32  2-Amino-N-(1-(8-chloro-5-(3-cyanopyrrolidin-1-yl)imidazo- [1,5-a]pyridin-6-yl)ethyl)-pyrazolo[1,5-a]pyrimidine-3- carboxamide trifluoroacetate salt(diastereomeric mixture prepared)

Calculated for C₂₁H₂₁ClN₉O (M + H)⁺: m/z = 450.2; found: 450.2 33 2-amino-N-(1-(8-chloro-5-(3- cyano-3-methylpyrrolidin-1-yl)imidazo[1,5-a]pyridin-6- yl)ethyl)pyrazolo[1,5-a]pyrim-idine-3-carboxamide trifluoro- acetate salt (diastereomeric mixtureprepared)

Calculated for C₂₂H₂₃ClN₉O (M + H)⁺: m/z = 464.2; found: 464.3 34 2-Amino-N-(1-(8-chloro-5- ((3S,4S)-3,4-dihydroxy-pyrrolidin-1-yl)imidazo[1,5- a]pyridin-6-yl)ethyl)pyrazolo-[1,5-a]pyrimidine-3-carbox- amide trifluoroacetate salt (diastereomericmixture prepared)

Calculated for C₂₀H₂₂ClN₈O₃ (M + H)⁺: m/z = 457.2; found: 457.2 35 2-Amino-N-(1-(8-chloro-5- ((3S,45)-3-fluoro-4-hydroxy-pyrrolidin-1-yl)imidazo[1,5- a]pyridin-6-yl)ethyl)pyrazolo-[1,5-a]pyrimidine-3-carbox- amide trifluoroacetate salt (diastereomericmixture prepared)

Calculated for C₂₀H₂₁ClFN₈O₂ (M + H)⁺: m/z = 459.1; found: 459.2 36 2-Amino-N-(1-[8-chloro-5- (1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6- yl]ethyl)pyrazolo[1,5-a]-pyrimidine-3-carboxamide trifluoroacetate salt (diastereomeric mixtureprepared)

Calculated for C₂₀H₂₂ClN₈O₃S (M + H)⁺: m/z = 489.1; found: 489.1  36A2-Amino-N-(1-[8-chloro-5- (1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6- yl]ethyl)pyrazolo[1,5-a]-pyrimidine-3-carboxamide (isomer 1)

Calculated for C₂₀H₂₂ClN₈O₃S (M + H)⁺: m/z = 489.1; found: 489.1 37 2-Amino-N-(1-[8-chloro-5-(1- oxidothiomorpholin-4-yl)-imidazo[1,5-a]pyridin-6-yl]- ethyl)pyrazolo[1,5-a]pyrim-idine-3-carboxamide trifluoro- acetate salt (diastereomeric mixtureprepared)

Calculated for C₂₀H₂₂ClN₈O₂S (M + H)⁺: m/z = 473.1; found: 473.1  38A2-Amino-N-(1-[8-chloro-5- (3-methyl-1,1-dioxidothio-morpholin-4-yl)imidazo- [1,5-a]pyridin-6-yl]ethyl)-pyrazolo[1,5-a]pyrimidine- 3-carboxamide trifluoro- acetate salt(diastereomeric mixture prepared) (Isomer 1)

Calculated for C₂₁H₂₄ClN₈O₃S (M + H)⁺: m/z = 503.1; found: 503.1  38B2-Amino-N(1-[8-chloro-5- (3-methyl-1,1-dioxidothio-morpholin-4-yl)imidazo[1,5- a]pyridin-6-yl]ethyl)pyrazolo-[1,5-a]pyrimidine-3-carbox- amide trifluoroacetate salt (diastereomericmixture prepared) (Isomer 2)

Calculated for C₂₁H₂₄ClN₈O₃S (M + H)⁺: m/z = 503.1; found: 503.1 39 2-Amino-N-(1-[8-chloro-5- (1-imino-1-oxidothio-morpholin-4-yl)imidazo[1,5- a]pyridin-6-yl]ethyl)pyrazolo-[1,5-a]pyrimidine-3-carbox- amide (diastereomeric mixture prepared)

Calculated for C₂₀H₂₃ClN₉O₂S (M + H)⁺: m/z = 488.1; found: 488.1 40 2-Amino-N-(1-[8-chloro-5- (2,2-dimethyl-1,1-dioxidothio-morpholin-4-yl)imidazo[1,5- a]pyridin-6-yl]ethyl)pyrazolo-[1,5-a]pyrimidine-3-carbox- amide trifluoroacetate salt (scalemicmixture prepared)

Calculated for C₂₂H₂₆ClN₈O₃S (M + H)⁺: m/z = 517.2; found: 517.2

TABLE 3a Ex. No. ¹H NMR Data 32 ¹H NMR (400 MHz, MeOD) δ 9.31 (m, 1H),8.72 (d, J = 6.8,, 1H), 8.59 (d, J = 4.5, 1H), 8.10 (s, 1H), 7.44 (s,1H), 7.02 (dd, J = 6.8, 4.5 Hz, 1H), 5.59-5.30 (m, 1H), 3.88 (m, 1H),3.71- 3.45 (m, 4H), 2.72-2.58 (m, 1H), 2.58-2.42 (m, 1H), 1.67 (dd, J =7.0, 1.7 Hz, 3H). 33 ¹H NMR (400 MHz, MeOD) δ 9.16 (s, 1H), 8.73 (d, J =6.7 Hz, 1H), 8.60 (d, J = 4.5 Hz, 1H), 8.03 (s, 1H), 7.39 (s, 1H),7.10-6.94 (m, 1H), 5.51 (s, 1H), 3.78 (m, 4H), 2.69 (m, 1H), 2.41 (m,1H), 1.79-1.56 (m, 6H). 36 ¹H NMR (400 MHz, MeOD) δ 9.53 (s, 1H), 8.70(dd, J = 6.8, 1.6 Hz, 1H), 8.57 (dd, J = 4.5, 1.6 Hz, 1H), 8.09 (s, 1H),7.43 (s, 1H), 6.99 (dd, J = 6.8, 4.5 Hz, 1H), 5.51 (q, J = 7.0 Hz, 1H),4.32-4.06 (m, 1H), 4.01-3.73 (m, 3H), 3.68-3.41 (m, 3H), 3.41-3.34 (m,1H), 1.68 (d, J = 7.0 Hz, 3H).

Example 41.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-5-(5-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1. Ethyl2-amino-5-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyrimidine-3-carboxylate

Trifluoromethanesulfonic anhydride (2 mL, 9 mmol) was added dropwise toethyl 2-amino-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate(0.7 g, 3 mmol) in dichloromethane (20 mL) and triethylamine (3 mL, 20mmol) at −78° C. The resulting mixture was stirred at −78° C. for 1 h.The reaction was quenched by adding sodium bicarbonate (sat.) at −78° C.The mixture was further diluted with dichloromethane (10 mL) and stirredfrom −78° C. to room temperature. After aqueous workup, the combinedorganic layer was dried over sodium sulfate, filtered, and concentratedunder vacuum. Purification by flash column chromatography (0-20%methanol in dichloromethane) afforded the desired product (0.09 g, 8%).LCMS calculated for C₁₀H₁₀F₃N₄O₅S (M+H)⁺: m/z=355.0; found: 355.0.

Step 2. Ethyl2-amino-5-(5-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

A suspension of ethyl2-amino-5-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyrimidine-3-carboxylate(0.02 g, 0.06 mmol),3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.017g, 0.073 mmol) (676624, Aldrich),dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium(0.004 g, 0.006 mmol), sodium carbonate (0.01 g, 0.1 mmol) in1,4-dioxane (2 mL) and water (0.5 mL) was degassed with nitrogen gas andthen heated at 80° C. for 1 h. The mixture was cooled to roomtemperature, diluted with methanol, filtered through Celite, andconcentrated under vacuum. The residue was purified by flash columnchromatography to afford the desired product (0.020 g, 100%). LCMScalculated for C₁₅H₁₆N₅O₃ (M+H)⁺: m/z=314.1; found: 314.0.

Step 3.2-Amino-5-(5-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

Lithium hydroxide (14 mg, 0.42 mmol) was added to a solution of ethyl2-amino-5-(5-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(0.014 g, 0.042 mmol) in methanol (1 mL). The mixture was heated to 80°C. for 2 h. The solvent was evaporated under vacuum. The residue wasused in the next step without purification. LCMS calculated for C₁₃H₁₂N₅O₃ (M+H)⁺: m/z=286.1; found: 286.1.

Step 4.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-5-(5-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To the mixture of crude2-amino-5-(5-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (from step 3), 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanamine(Examples 3a-3b, Step 1, 0.010 g, 0.042 mmol) andN,N-diisopropylethylamine (20 uL, 0.1 mmol) in anhydrousN,N-dimethylformamide (1 mL) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.016 g, 0.042 mmol) and the resultant mixture wasstirred at room temperature for 1 h. Ice-water (0.2 mL) was added to thereaction mixture and then stirred for 10 min. The mixture was dilutedwith methanol (4 mL). Purification by preparative LCMS (pH 10) affordedthe desired product (9 mg, 20% over two steps). LCMS calculated forC₂₄H₂₄ClN₈O₃ (M+H)⁺: m/z=507.2; found: 507.1.

Example 42.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-5-(5-(hydroxymethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

This compound was synthesized according to the procedure of Example 41,using [5-(hydroxymethyl)pyridin-3-yl]boronic acid (BB-3541,Combi-Blocks) to replace3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as oneof the starting materials in step 2. LCMS calculated for C₂₄H₂₄ClN₈O₃(M+H)⁺: m/z=507.2; found: 507.2.

Example 43.2-Amino-N-(1-(3,4-dichloro-7-ethoxy-1H-indazol-6-yl)ethyl)-5-(5-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt

Step 1. 1-(3,4-dichloro-7-ethoxy-1H-indazol-6-yl)ethanone

To a solution of 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanone (90 mg,0.4 mmol) in N,N-dimethylformamide (2 mL) was added N-chlorosuccinimide(76 mg, 0.56 mmol) at room temperature. After stirring for 4 h, thereaction mixture was diluted with EtOAc, washed with sodium carbonate(sat.), dried over sodium sulfate and concentrated under vacuum.Purification by flash column chromatography afforded the desiredproduct. LCMS calculated for C₁₁H₁₁Cl₂N₂O₂ (M+H)⁺: m/z=273.0; found:273.0.

Step 2. 1-(3,4-Dichloro-7-ethoxy-1H-indazol-6-yl)ethanamine

To a solution of 1-(3,4-dichloro-7-ethoxy-1H-indazol-6-yl)ethanone (0.10g, 0.37 mmol) in 2.0 M ammonia in ethanol (4 mL, 8 mmol) was addedtitanium tetraisopropoxide (300 μL, 1 mmol). The reaction mixture washeated at 80° C. for 3 h and then cooled to 0° C. Sodiumtetrahydroborate (40 mg, 1 mmol) was added to the mixture. Afterstirring for 0.5 h, the reaction was quenched with ammonium hydroxide (1M), filtered, and the solid was washed with acetonitrile. The volatileswere removed in vacuo, and the residue dissolved in EtOAc and washedwith water and brine. The organic layer was dried over sodium sulfate,filtered, and concentrated under vacuum. The crude product was useddirectly in the next step without purification. LCMS calculated forC₁₁H₁₄Cl₂N₃O (M+H)⁺: m/z=274.1; found: 274.0.

Step 3.2-Amino-5-(5-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

This compound was synthesized according to the procedure of Example 41,using 1-(3,4-dichloro-7-ethoxy-1H-indazol-6-yl)ethanamine to replace1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanamine as the starting materialin step 4. LCMS calculated for C₂₄H₂₃Cl₂N₈O₃ (M+H)⁺: m/z=541.1; found:541.1 ¹H NMR (400 MHz, DMSO) δ 13.76 (s, 1H), 9.12-8.98 (m, 2H), 8.49(d, J=2.7 Hz, 1H), 8.25 (d, J=6.9 Hz, 1H), 8.15 (s, 1H), 7.74 (d, J=7.1Hz, 1H), 7.29 (s, 1H), 5.68-5.23 (m, 1H), 4.45-4.02 (m, 2H), 3.95 (s,3H), 1.59 (d, J=6.9 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H).

Example 44.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-5-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt

Step 1. 2-Amino-5-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

To a solution of ethyl2-amino-5-{[(trifluoromethyl)sulfonyl]oxy}pyrazolo[1,5-a]pyrimidine-3-carboxylate(Example 43, Step 1, 20 mg, 0.056 mmol) in acetonitrile (0.6 mL) wasadded piperidine (0.017 mL, 0.17 mmol) and N,N-diisopropylethylamine(0.1 mL, 0.6 mmol). The resultant mixture was stirred at 80° C. for 1 h.To the mixture was added lithium hydroxide in water (4.0 M, 0.1 mL, 0.6mmol). The resultant mixture was heated at 80° C. for 1 h. The solventwas removed and the residue was purified by preparative LCMS (pH 10) toafford the desired product (14 mg, 95% yield). LCMS calculated forC₁₂H₁₆N₅O₂ (M+H)⁺: m/z=262.1; found: 262.0.

Step 2.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-5-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt

To a vial containing 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanaminetrifluoroacetic acid (5.4 mg, 0.015 mmol),2-amino-5-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(4.0 mg, 0.015 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (5.8 mg, 0.015 mmol) was added N,N-dimethylformamide(0.7 mL), followed by dropwise addition f N,N-diisopropylethylamine (10μL, 0.08 mmol) at room temperature. After stirring for 1 h, ice-water(0.2 mL) was added to the reaction mixture and stirred for 10 min. Themixture was diluted with methanol (4 mL). Purification by preparativeLCMS (pH 2) afforded the desired product. LCMS calculated forC₂₃H₂₈ClN₈O₂ (M+H)⁺: m/z=483.2; found: 483.2.

Example 45.2-Amino-6-chloro-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)imidazo[1,2-b]pyridazine-3-carboxamide

Step 1. 6-chloro-3-iodoimidazo[1,2-b]pyridazin-2-amine

To a solution of 6-chloroimidazo[1,2-b]pyridazin-2-amine (0.50 g, 2.96mmol) (32325, Affinity Research Chemicals) in NN-Dimethylformamide (20mL) at 0° C. was added N-iodosuccinimide (0.80 g, 3.6 mmol). Theresulting solution was stirred at room temperature for 1 h. Water (20mL) was added to quench the reaction. After aqueous work up, thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated under vaccum. Purification with flash column chromatographyafforded the desired product (0.87 g, 62% yield). LCMS calculated forC₆H₅ClIN₄ (M+H)⁺: m/z=294.9; found: 294.8.

Step 2. Methyl 2-amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate

In a 40 mL vial, 6-chloro-3-iodoimidazo[1,2-b]pyridazin-2-amine (300 mg,1.0 mmol) in methanol (20 mL) and triethylamine (0.52 mL, 3.8 mmol) wasdegassed with a stream of nitrogen for 5 min. To the solution was added[1, F-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (40 mg, 0.05 mmol). The solution wassaturated with carbon monoxide by bubbling the carbon monoxide gasthrough the reaction subsurface for 3 min. The vessel was sealed andheated to 55° C. for 12 h. The reaction was cooled to room temperatureand the solvents were removed under vacuum. Purification by flash columnchromatography afforded the desired product (0.12 g, 52% yield). LCMScalculated for C₈H₈ClN₄O₂ (M+H)⁺: m/z=227.0; found: 227.0.

Step 3. 2-Amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid

A mixture of methyl2-amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (15 mg, 0.066mmol) and lithium hydroxide (8 mg, 0.3 mmol) in tetrahydrofuran (1 mL)and water (0.050 mL) was heated at 80° C. for 3 h. The reaction mixturewas cooled to room temperature and diluted with methanol (4 mL).Purification by preparative LCMS (pH 10) afforded the desired product(14 mg, 60% yield). LCMS calculated for C₇H₆ClN₄O₂ (M+H)⁺: m/z=213.0;found: 213.0.

Step 4.2-Amino-6-chloro-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)imidazo[1,2-b]pyridazine-3-carboxamide

To a mixture of 2-amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylicacid (20 mg, 0.09 mmol), 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanamine(Examples 3a-3b, Step 1, 32 mg, 0.13 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (43 mg, 0.11 mmol) in N,N-dimethylformamide (2.4 mL)was added N,N-diisopropylethylamine (50 μL, 0.3 mmol) and the resultantmixture was stirred at room temperature for 1 h. Ice-water was added tothe reaction mixture and then stirred for 10 min. The mixture wasfurther diluted with methanol (4 mL). Purification by preparative LCMS(pH10) afforded the desired product. (14 mg, 60% yield). LCMS calculatedfor C₁₈H₁₈Cl₂N₇O₂ (M+H)⁺: m/z=434.1; found: 434.2.

Example 46.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-6-methylimidazo[1,2-b]pyridazine-3-carboxamide

Step 1. Methyl 2-amino-6-methylimidazo[1,2-b]pyridazine-3-carboxylate

To a vial containing the mixture of trimethylboroxine (25 μL, 0.18mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (6 mg, 0.008 mmol), and potassium phosphate (56 mg, 0.26 mmol) wasadded a solution of methyl2-amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (Example 45, Step2, 0.020 g, 0.088 mmol) in 1,4-dioxane (1 mL) and water (100 μL). Thereaction was degassed with nitrogen and stirred at 50° C. for 5 h. Aftercooling to room temperature, the mixture was diluted with methanol (4mL) and purified by preparative LCMS (pH 10) to afford the desiredproduct (12.0 mg, 67% yield). LCMS calculated for C₉H₁₁N₄O₂ (M+H)⁺:m/z=207.1; found: 207.1

Step 2. 2-Amino-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acid

This compound was synthesized according to the procedure of Example 45,step 3, using methyl2-amino-6-methylimidazo[1,2-b]pyridazine-3-carboxylate to replace methyl2-amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate as the startingmaterial. LCMS calculated for C₈H₉N₄O₂ (M+H)⁺: m/z=193.1; found: 193.1.

Step 3.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-6-methylimidazo[1,2-b]pyridazine-3-carboxamide

This compound was synthesized according to the procedure of Example 45,step 4, using 2-amino-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acidto replace 2-amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid asthe starting material. LCMS calculated for C₁₉H₂₁ClN₇O₂ (M+H)⁺:m/z=414.1; found: 414.1.

Example 47.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-6-(piperidin-1-yl)imidazo[1,2-b]pyridazine-3-carboxamide

This compound was synthesized according to the procedure of Example 44,using methyl 2-amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate(Example 45, Step 2) to replace ethyl2-amino-5-{[(trifluoromethyl)sulfonyl]oxy}pyrazolo[1,5-a]pyrimidine-3-carboxylateas one of the starting materials in step 1. LCMS calculated forC₂₃H₂₈ClN₈O₂(M+H)⁺: m/z=483.2; found: 483.2.

Example 48.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-6-(5-(hydroxymethyl)pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Step 1. Methyl2-amino-6-(5-(hydroxymethyl)pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxylate

A suspension of methyl2-amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (Example 45, Step2, 0.02 g, 0.09 mmol), [5-(hydroxymethyl)pyridin-3-yl]boronic acid(0.018 g, 0.11 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.003 g,0.004 mmol), sodium carbonate (0.028 g, 0.26 mmol) in 1,4-dioxane (1 mL)and water (0.2 mL) was degassed by bubbling nitrogen. The mixture washeated to 80° C. and stirred for 1 h. After cooling to room temperature,the mixture was diluted with methanol (8 mL), filtered through Celite,and concentrated under vacuum. Purification by flash columnchromatography afforded the desired product. (20.0 mg, 80% yield). LCMScalculated for C₁₄H₁₄N₅O₃ (M+H)⁺: m/z=300.1; found: 300.1.

Step 2. 2-Amino-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acid

This compound was synthesized according to the procedure of Example 45,step 3, using methyl2-amino-6-(5-(hydroxymethyl)pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxylateto replace methyl 2-amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylateas the starting material. LCMS calculated for C₁₃ H₁₂N₅O₃ (M+H)⁺:m/z=286.1; found: 286.1.

Step 3.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-6-methylimidazo[1,2-b]pyridazine-3-carboxamide

This compound was synthesized according to the procedure of Example 45,step 4, using 2-amino-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acidto replace 2-amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid asthe starting material. LCMS calculated for C₂₄H₂₄ClN₈O₃ (M+H)⁺:m/z=507.2; found: 507.1.

Example 49.2-Amino-N-(1-(3,4-dichloro-7-ethoxy-1H-indazol-6-yl)ethyl)-6-(5-(hydroxymethyl)pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide

This compound was synthesized according to the procedure of Example 48,using 1-(3,4-dichloro-7-ethoxy-1H-indazol-6-yl)ethanamine (Example 43,Step 2) to replace 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanamine asthe starting material in step 3. LCMS calculated for C₂₄H₂₃Cl₂N₈O₃(M+H)⁺: m/z=541.1; found: 541.1.

Example 50.2-Amino-N-[1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl]-5-pyridin-3-ylpyrazolo[1,5-a]pyrimidine-3-carboxamidebis(trifluoroacetate)

This compound was synthesized according to the procedure of Example 41,using 3-pyridylboronic acid to replace3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as oneof the starting materials in step 2. LCMS calculated for C₂₃H₂₂ClN₈O₂(M+H)⁺: m/z=477.2; found: 477.2.

Example 51.2-Amino-N-(1-(4-chloro-3-ethyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. 1-(4-chloro-3-ethyl-7-phenyl-JH-indazol-6-yl)ethanone

To a solution of 1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethanone(60.0 mg, 0.172 mmol, from Example 23, Step 1) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (6 mg,0.008 mmol) in dioxane (1 mL) was added 1.0 M diethyl zinc in hexanes(0.26 mL, 0.26 mmol) at room temperature and the reaction mixture washeated to 80° C. for 2 h. After cooling to room temperature, thevolatiles were evaporated in vacuo and the residue was purified by flashchromatography (0-30% EtOAc/hexanes) to afford the title compound as awhite solid (27 mg, 53%), contaminated with a minor amount of thebis-ethylated product (from C1 coupling). LCMS calculated forC₁₇H₁₆ClN₂O (M+H)⁺: m/z=299.1; found: 299.1.

Step 2. 1-(4-chloro-3-ethyl-7-phenyl-1H-indazol-6-yl)ethanamine

This compound was synthesized according to the procedure described inExample 23, Step 2, starting from1-(4-chloro-3-ethyl-7-phenyl-1H-indazol-6-yl)ethanone (27 mg, 0.090mmol). The product was used without purification (theoretical yieldassumed). LCMS calculated for C₁₇H₁₆ClN₂ (M−NH₂)⁺: m/z=283.1; found:283.1.

Step 3.2-amino-N-(1-(4-chloro-3-ethyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

To a vial containing1-(4-chloro-3-ethyl-7-phenyl-1H-indazol-6-yl)ethanamine (27 mg, 0.090mmol),2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (28 mg, 0.099 mmol, from J&W Pharmlab), andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (38 mg, 0.099 mmol) was added DMF (2 mL), followedby dropwise addition of N,N-diisopropylethylamine (0.047 mL, 0.27 mmol)at room temperature. After stirring for 1 h, the reaction mixture wasdiluted with EtOAc (10 mL) and quenched with water (5 mL). The layerswere separated, and the organic layer was dried over MgSO₄, filtered,and concentrated. The residue was stirred with TFA (1 mL) in CH₂Cl₂ (2mL) for 0.5 h. The volatiles were removed in vacuo and the residue wasdissolved in MeOH and purified by preparative HPLC (pH 2). ¹H NMR (600MHz, DMSO) δ 8.92 (dd, J=6.7, 1.6 Hz, 1H), 8.56 (dd, J=4.5, 1.6 Hz, 1H),8.11 (d, J=6.8 Hz, 1H), 7.62 (br s, 1H), 7.57 (br s, 2H), 7.53-7.47 (m,1H), 7.39 (br s, 1H), 7.21 (s, 1H), 7.01 (dd, J=6.7, 4.5 Hz, 1H), 5.07(p, J=6.9 Hz, 1H), 3.08 (q, J=7.5 Hz, 2H), 1.36 (d, J=6.9 Hz, 3H), 1.30(t, J=7.5 Hz, 3H). LCMS calculated for C₂₄H₂₃ClN₇O (M+H)⁺: m/z=460.2;found: 460.1.

Example 52.2-Amino-N-(1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. 1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethanone

To a solution of 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanone (100 mg,0.419 mmol, from Example 1, Step 3) in DMF (2 mL) was addedN-bromosuccinimide (89 mg, 0.50 mmol) at room temperature. Afterstirring for 2 h, the reaction mixture was quenched with saturatedaqueous NaHCO₃ and extracted with EtOAc. The organic layer was driedover MgSO₄, filtered, and concentrated to afford an orange solid thatwas used without purification. LCMS calculated for C₁₁H₁₁BrClN₂O₂(M+H)⁺:m/z=317.0; found: 316.9.

Step 2. 1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethanamine

This compound was synthesized according to the procedure described inExample 23, Step 2, starting from1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethanone (120 mg, 0.380mmol). The product was used without purification (theoretical yieldassumed). LCMS calculated for C₁₁H₁₁BrClN₂O (M−NH₂)⁺: m/z=301.0; found:300.9.

Step 3. tert-butyl3-(1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate

This compound was synthesized according to the procedure described inExample 1, Step 6, starting from1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethanamine (120 mg, 0.380mmol). The residue was purified by flash chromatography (0-100%EtOAc/hexanes) to afford the product as an off white solid. LCMScalculated for C₂₃H₂₆BrClN₇O₄(M+H)⁺: m/z=578.1; found: 578.0.

Step 4.2-amino-N-(1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate.

This compound was synthesized according to the procedure described inExample 1, Step 7, starting from tert-butyl3-(1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate(10 mg, 0.02 mmol). The residue was purified by preparative HPLC (pH 2)to afford the product as a white solid. ¹H NMR (600 MHz, DMSO) δ 13.92(s, 1H), 8.92 (dd, J=6.7, 1.6 Hz, 1H), 8.56 (dd, J=4.5, 1.6 Hz, 1H),8.18 (d, J=7.5 Hz, 1H), 7.18 (s, 1H), 7.01 (dd, J=6.7, 4.5 Hz, 1H), 6.45(br s, 2H), 5.51 (p, J=7.0 Hz, 1H), 4.28-4.19 (m, 2H), 1.52 (d, J=7.0Hz, 3H), 1.45 (t, J=7.0 Hz, 3H). LCMS calculated for C₁₈H₁₈BrClN₇O₂(M+H)⁺: m/z=478.1; found: 478.0.

Examples 53-54.2-Amino-N-(1-(3-bromo-4-chloro-7-ethoxy-2-(2-hydroxyethyl)-2H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Example 53) &2-Amino-N-(1-(3-bromo-4-chloro-7-ethoxy-1-(2-hydroxyethyl)-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate (Example 54)

To a solution of tert-butyl3-(1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate(35 mg, 0.060 mmol, from Example 52, Step 3) in DMF (1 mL) was addedpotassium carbonate (40 mg, 0.3 mmol), followed by 2-iodoethanol (50 μL,0.60 mmol) and the reaction mixture was heated to 70° C. overnight.After cooling to room temperature, the mixture was diluted with EtOAcand washed with water. The organic layer was washed with brine, driedover MgSO₄, filtered, and concentrated. The residue was dissolved in DCM(2 mL), and TFA (1 mL) was added. After stirring for 0.5 h, thevolatiles were removed in vacuo and the residue was purified bypreparative HPLC (pH 2) to afford the title compounds, which werereadily separable (36.1-56.1% MeCN/water gradient). Peak 1 (Example 53):Retention time=5.05. LCMS calculated for C₂₀H₂₂BrClN₇O₃ (M+H)⁺:m/z=522.1; found: 522.1. Peak 2 (Example 54): Retention time=5.68. LCMScalculated for C₂₀H₂₂BrClN₇O₃ (M+H)⁺: m/z=522.1; found: 522.1.

Example 55.2-Amino-N-(1-(4-chloro-3-cyano-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. 1-(4-chloro-3-iodo-7-phenyl-1H-indazol-6-yl)ethanone

To a solution of 1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethanone (Example14, Step 4, 500 mg, 1.85 mmol) in DMF (9 mL) was added N-iodosuccinimide(540 mg, 2.4 mmol) and the reaction mixture was stirred overnight. Thereaction was quenched with saturated NaHCO₃ and extracted with EtOAc.The organic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography (O-35%EtOAc/hexanes) to afford the title compound (640 mg, 87%) as an offwhite solid. LCMS calculated for C₁₅H₁₁ClIN₂O (M+H)⁺: m/z=397.0; found:396.9.

Step 2. methyl 6-acetyl-4-chloro-7-phenyl-1H-indazole-3-carboxylate

A solution of 1-(4-chloro-3-iodo-7-phenyl-1H-indazol-6-yl)ethanone (40mg, 0.101 mmol), Pd(dppf)Cl₂ (4 mg, .005 mmol), and triethylamine (42μL, 0.30 mmol) in DMF (1.6 mL) and MeOH (0.4 mL) was saturated with COfor 10 min. The reaction mixture was then heated at 90° C. under balloonpressure of CO overnight. The volatiles were evaporated and the residuewas purified by flash chromatography (0-40% EtOAc/hexanes) to afford thetitle compound (33 mg, quant.) as a yellow oil. LCMS calculated forC₁₇H₁₄ClN₂O₃(M+H)⁺: m/z=329.1; found: 329.0.

Step 3. 6-acetyl-4-chloro-7-phenyl-1H-indazole-3-carboxylic acid

To a solution of methyl6-acetyl-4-chloro-7-phenyl-1H-indazole-3-carboxylate (33.0 mg, 0.100mmol) in THF/methanol/water (1:1:1) was added sodium hydroxide (40 mg, 1mmol) and the reaction mixture was heated at 65° C. for 4 h. Aftercooling to room temperature, the volatiles were evaporated in vacuo andthe residue was treated with 1M HCl, forming a precipitate, which wassolubilized by addition of EtOAc. The solution was diluted withadditional EtOAc and 1M HCl, and the layers were separated. The organiclayer was washed with brine, dried over MgSO₄, filtered and concentratedto afford the title compound (31 mg, 98%) that was used withoutpurification. LCMS calculated for C₁₆H₁₂ClN₂O₃(M+H)⁺: m/z=315.1; found:315.0.

Step 4. 6-acetyl-4-chloro-7-phenyl-1H-indazole-3-carboxamide

To a mixture of 6-acetyl-4-chloro-7-phenyl-1H-indazole-3-carboxylic acid(31.0 mg, 0.0985 mmol), ammonium chloride (10 mg, 0.20 mmol), and HATU(75 mg, 0.20 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (86μL, 0.49 mmol) at room temperature. After stirring overnight, thereaction mixture was diluted with EtOAc and quenched with water. Thelayers were separated and the aqueous layer was extracted with EtOAc.The combined organic layers were washed with brine, dried over MgSO₄ andconcentrated. The residue was purified by flash chromatography (0-100%EtOAc/hexanes) to afford the product as a white solid, still containingresidual DMF. Quantitative yield was assumed. LCMS calculated forC₁₆H₁₃ClN₃O₂(M+H)⁺: m/z=314.1; found: 314.0.

Step 5. 6-acetyl-4-chloro-7-phenyl-IH-indazole-3-carbonitrile

To a suspension of 6-acetyl-4-chloro-7-phenyl-1H-indazole-3-carboxamide(30.0 mg, 0.0956 mmol) in CH₂Cl₂ (39 mmol) at 0° C. was added Et₃N (40μL, 0.29 mmol), followed by dropwise addition of 1.0 Mtrifluoromethanesulfonic anhydride (1M/CH₂Cl₂, 0.29 mL, 0.29 mmol).During the addition, the white suspension gradually became a yellow,then deep red solution. After the addition was complete, the ice bathwas removed and the solution was stirred at room temperature for 1 h.The reaction was quenched with saturated NaHCO₃ and the resultingmixture was extracted with DCM. The organic layer was dried over MgSO₄,filtered, and concentrated. The residue was purified by flashchromatography (0-45% EtOAc/hexanes) to afford the title compound (8.2mg, 29%) as a reddish solid. LCMS calculated for C₁₆H₁₁ClN₃O (M+H)⁺:m/z=296.0; found: 296.0.

Step 6. 6-(1-aminoethyl)-4-chloro-7-phenyl-1H-indazole-3-carbonitrile

This compound was synthesized according to the procedure described inExample 23, Step 2, starting from6-acetyl-4-chloro-7-phenyl-1H-indazole-3-carbonitrile (8.0 mg, 0.027mmol). The product was used without purification (theoretical yieldassumed). LCMS calculated for C₁₆H₁₁ClN₃ (M−NH₂)⁺: m/z=280.0; found:280.0.

Step 7.2-amino-N-(1-(4-chloro-3-cyano-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

This compound was synthesized according to the procedure described inExample 26, Step 3, starting from6-(1-aminoethyl)-4-chloro-7-phenyl-1H-indazole-3-carbonitrile (8.0 mg,0.027 mmol). The residue was purified by preparative HPLC (pH 2) toafford the title compound as a white solid (2.5 mg, 20%). LCMScalculated for C₂₃H₁₈ClN₈O (M+H)⁺: m/z=457.1; found: 457.1.

Example 56.2-Amino-N-(1-(4-chloro-7-(4-cyanopiperidin-1-yl)pyrazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. 1-amino-2-methoxypyridinium 2, 4-dinitrobenzenolate

To a solution of O-(2,4-dinitrophenyl)hydroxylamine (9.1 g, 46 mmol) inacetonitrile (30 mL, 600 mmol) was added 2-methoxypyridine (4.8 mL, 46mmol) and the reaction mixture was heated to 40° C. over the weekend.The solvent was removed in vacuo and the solid was filtered, washed withdiethyl ether (20 mL), and dried to yield the title compound (9.17 g,65%) as a light orange solid. ¹H NMR (400 MHz, DMSO) δ 8.61 (d, J=3.1Hz, 1H), 8.56 (dd, J=6.5, 1.4 Hz, 1H), 8.32-8.22 (m, 1H), 7.85 (dd,J=9.7, 3.1 Hz, 1H), 7.74-7.71 (m, 3H), 7.55-7.44 (m, 1H), 6.43 (d, J=9.7Hz, 1H), 4.27 (s, 3H). LCMS calculated for C₆H₉N₂O (M)⁺: m/z=125.1;found 125.1.

Step 2. ethyl 7-methoxypyrazolo[1,5-a]pyridine-3-carboxylate

To a suspension of 1-amino-2-methoxypyridinium 2,4-dinitrobenzenolate(9.17 g, 29.7 mmol) in DMF (79 mL) was added potassium carbonate (6.2 g,45 mmol), followed by dropwise addition of ethyl propiolate (4.5 mL, 45mmol) at room temperature. After stirring for 2 h the reaction mixturewas poured into water and diluted with EtOAc. The layers were separatedand the aqueous layer was extracted with EtOAc. The combined organiclayers were washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography (O-60%EtOAc/hexanes) to afford the title compound (3.1 g, 47%) as a beigesolid. ¹H NMR (400 MHz, DMSO) δ 8.42 (s, 1H), 7.69 (dd, J=8.7, 1.0 Hz,1H), 7.65-7.57 (m, 1H), 6.70-6.63 (m, 1H), 4.30 (q, J=7.1 Hz, 2H), 4.15(s, 3H), 1.34 (t, J=7.1 Hz, 3H). LCMS calculated for C₁₁H₁₃N₂O₃ (M+H)⁺:m/z=221.1; found 221.1.

Step 3. ethyl 6-chloro-7-methoxypyrazolo[1,5-a]pyridine-3-carboxylate

To a solution of ethyl 7-methoxypyrazolo[1,5-a]pyridine-3-carboxylate(294 mg, 1.34 mmol) in DMF (6.0 mL) was added N-chlorosuccinimide (187mg, 1.40 mmol) and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was diluted with EtOAc and washed withwater and brine. The organic layer was dried over MgSO₄ andconcentrated, and the residue was purified by flash chromatography(0-15% EtOAc/hexanes) to afford the title compound (237 mg, 70%) as anoff white solid. ¹H NMR (400 MHz, DMSO) δ 8.51 (s, 1H), 7.83 (d, J =9.4Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 4.22 (s, 3H),1.34 (t, J=7.1 Hz, 4H). LCMS calculated for C₁₁H₁₂ClN₂O₃ (M+H)⁺:m/z=255.1; found 255.1.

Step 4. ethyl 6-acetyl-7-methoxypyrazolo[1,5-a]pyridine-3-carboxylate

To a mixture of ethyl6-chloro-7-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (237.0 mg, 0.93mmol), cesium fluoride (280 mg, 1.9 mmol), and XPhos Pd G2 (70 mg, 0.09mmol) in 1,4-dioxane (5.0 mL) was added tributyl(1-ethoxyvinyl)tin (0.38mL, 1.1 mmol) and the reaction mixture was heated to reflux for 4 h.After cooling to room temp, 1M HCl was added and the reaction mixturewas stirred for 1 h. The reaction mixture was partitioned between waterand EtOAc, and the layers were separated. The organic layer was washedwith brine, dried over MgSO₄, filtered, and concentrated. The residuewas purified by flash chromatography (0-30% EtOAc/hexanes) to afford thetitle compound (621 mg, 91%) as a white solid. LCMS calculated forC₁₃H₁₅N₂O₄ (M+H)⁺: m/z=263.1; found 263.1.

Step 5. ethyl6-acetyl-7-amino-4-chloropyrazolo[1,5-a]pyridine-3-carboxylate

A solution of ethyl6-acetyl-7-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (300.0 mg, 1.144mmol) in 2.0 M ammonia in ethanol (7.0 mL, 14 mmol) was heated to 60° C.for 2 h. The volatiles were removed in vacuo, the resulting solid wassuspended in acetic acid (9.0 mL, 160 mmol) and N-chlorosuccinimide (460mg, 3.4 mmol) was added. The reaction mixture was heated to 45° C. for 3h. The reaction mixture was partitioned between water and EtOAc, and thelayers were separated. The aqueous layer was extracted with EtOAc andthe combined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by flashchromatography (0-25% EtOAc/hexanes) to afford the title compound (208mg, 65%). LCMS calculated for C₁₂H₁₃ClN₃O₃ (M+H)⁺: m/z=282.1; found282.1.

Step 6. ethyl 6-acetyl-4,7-dichloropyrazolo[1,5-a]pyridine-3-carboxylate

Ethyl 6-acetyl-7-amino-4-chloropyrazolo[1,5-a]pyridine-3-carboxylate(413 mg, 1.47 mmol) was dissolved in conc. HCl (6.0 mL) and acetic acid(6.0 mL) and cooled to 0° C. A solution of sodium nitrite (300 mg, 4.4mmol) in water (1.0 mL) was added dropwise, and the solution changedfrom yellow to dark green. After 0.5 h, the reaction mixture was dilutedwith water and EtOAc, and the layers were separated. The organic layerwas washed with brine, dried over MgSO₄, and concentrated. The resultingdark brown solid was washed with hexanes, filtered, and air dried toafford the title compound (410 mg, 93%) as a light brown solid. LCMScalculated for C₁₂H₁₁Cl₂N₂O₃ (M+H)⁺: m/z=301.0; found 301.0.

Step 7. 1-(4,7-dichloropyrazolo[1,5-a]pyridin-6-yl)ethanone

Ethyl 6-acetyl-4,7-dichloropyrazolo[1,5-a]pyridine-3-carboxylate (410mg, 1.4 mmol) was taken up in 6M HCl (6.0 mL) and acetic acid (6.0 mL),and heated to 100° C. overnight. After cooling to room temp, thereaction mixture was partitioned between water and EtOAc, and the layerswere separated. The organic layer was washed with brine, dried overMgSO₄, and concentrated. The residue was purified by flashchromatography (0-20% EtOAc/hexanes) to afford the title compound (296mg, 95%) as a yellow solid. LCMS calculated for C₉H₇Cl₂N₂O (M+H)⁺:m/z=229.0; found 229.0.

Step 8.1-(6-acetyl-4-chloropyrazolo[1,5-a]pyridin-7-Apperidine-4-carbonitrile

A mixture of 1-(4,7-dichloropyrazolo[1,5-a]pyridin-6-ypethanone (15.0mg, 0.065 mmol), piperidine-4-carbonitrile (11 μL, 0.098 mmol), andcesium carbonate (43 mg, 0.13 mmol) was taken up in acetonitrile (2.0mL, 38 mmol) and heated to 70° C. for 1.5 h. The reaction mixture waspartitioned between EtOAc and water, and the layers were separated. Theorganic layer was washed with brine, dried over MgSO₄ and concentrated.The residue was used without purification (theoretical yield assumed).LCMS calculated for C₁₅H₁₆ClN₄O (M+H)⁺: m/z=303.1; found 303.1.

Step 9.2-amino-N-(1-(4-chloro-7-(4-cyanopiperidin-1-yl)pyrazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

To a solution of1-(6-acetyl-4-chloropyrazolo[1,5-a]pyridin-7-yl)piperidine-4-carbonitrile(19.0 mg, 0.0628 mmol) in 2.0 M ammonia in ethanol (3.0 mL, 6.0 mmol)was added titanium tetraisopropoxide (56 ηL, 0.19 mmol) and the reactionmixture was heated at 60° C. overnight. The resulting solution wascooled to room temperature, then 0° C., and sodium borohydride (7.1 mg,0.19 mmol) was added. After stirring for 0.5 h, the reaction wasquenched with 1M NH₄OH, filtered, and the solid was washed with EtOAc.The filtrate was washed with water, brine, dried over MgSO₄, andconcentrated. The product was used without purification. To a vialcontaining the crude amine,2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (21 mg, 0.075 mmol), and HATU (29 mg, 0.075 mmol) was added DMF (3mL), followed by dropwise addition of N,N-diisopropylethylamine (33 μL,0.19 mmol) at room temperature. After stirring for 1 h, the reaction wasquenched with water and extracted with EtOAc. The organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was dissolved in DCM (2 mL) and TFA (1.0 mL, 13 mmol) was addedat room temp. After stirring for 1 h, the volatiles were evaporated invacuo and the residue was purified by prep HPLC (pH 2) to afford thetitle compound (11.2 mg, 39%) as a white solid. LCMS calculated forC₂₂H₂₃ClN₉O (M+H)⁺: m/z=464.2; found 464.2.

Example 57-58.(S)-2-Amino-N-(1-(4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate (Example 57) &(S)-2-Amino-N-(1-(4-chloro-7-(1,1-dioxidothiomorpholino)-3-fluoropyrazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate (Example 58)

Step 1. 1-(4,7-dichloropyrazolo[1,5-a]pyridin-6-yl)ethanone &1-(4,7-dichloro-3-fluoropyrazolo[1,5-a]pyridin-6-yl)ethanone

To a solution of 1-(4,7-dichloropyrazolo[1,5-a]pyridin-6-yl)ethan-1-one(820 mg, 3.58 mmol, from Example 56, Step 7) in acetonitrile (7.0 ml)was added Selectfluor (2.54 g, 7.16 mmol) and the reaction mixture wasstirred at room temperature for 8.5 h. The reaction mixture was dilutedwith EtOAc and washed with water and brine. The organic layer was driedover MgSO₄, filtered, and concentrated. The residue was purified byflash chromatography (0-10% EtOAc/hexanes) to afford a 1:1 mixture ofthe title compounds (701 mg, 79%). Peak 1: LCMS calculated forC₉H₇Cl₂N₂O (M+H)⁺: m/z=229.0; found 229.0. Peak 2: LCMS calculated forC₉H₆Cl₂FN₂O (M+H)⁺: m/z=247.0; found 247.0.

Step 2.1-(4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridin-6-yl)ethan-1-one&1-(4-chloro-7-(1,1-dioxidothiomorpholino)-3-fluorophyrazolo[1,5-a]pyridin-6-yl)ethan-1-one

A 1:1 mixture of 1-(4,7-dichloropyrazolo[1,5-a]pyridin-6-yl)ethan-1-oneand 1-(4,7-dichloro-3-fluoropyrazolo[1,5-a]pyridin-6-yl)ethan-1-one (701mg, -3.06 mmol), thiomorpholine dioxide (827 mg, 6.12 mmol), and DIPEA(1.069 ml, 6.12 mmol) was heated to 140° C. in the microwave for 1 h.LCMS indicated complete conversion to the desired product. The reactionmixture was diluted with EtOAc, washed with water and brine, dried overMgSO₄ and concentrated. The residue was used without purification. Peak1: LCMS calculated for C₁₃H₁₅ClN₃O₃S (M+H)⁺: m/z=328.0; found 328.0.Peak 2: LCMS calculated for C₁₃H₁₄ClFN₃O₃S (M+H)⁺: m/z=346.0; found346.0.

Step 3.N-((S)-1-(4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridin-6-yl)ethyl)-2-methylpropane-2-sulfinamide&N-((S)-1-(4-chloro-7-(1,1-dioxidothiomorpholino)-3-fluoropyrazolo[1,5-a]pyridin-6-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of1-(4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridin-6-yl)ethan-1-oneand1-(4-chloro-7-(1,1-dioxidothiomorpholino)-3-fluoropyrazolo[1,5-a]pyridin-6-yl)ethan-1-one(1.03 g, ˜3.14 mmol), and (S)-2-methylpropane-2-sulfinamide (3.81 g,31.4 mmol) in cyclopentyl methyl ether (20 ml) was added titanium(IV)isopropoxide (2.76 ml, 9.43 mmol) and the reaction mixture was heated to100° C. overnight. The resulting mixture of sulfinimines was cooled to0° C. and sodium borohydride (1.189 g, 31.4 mmol) was added in severalportions. The reaction mixture was allowed to warm to room temperatureand a small amount of EtOH (˜0.5 mL) was added dropwise. After stirringfor 0.5 h, LCMS indicated complete conversion (6:1 d.r. for bothcompounds). The reaction mixture was cooled to 0° C., quenched by thedropwise addition of MeOH, and vigorously stirred until no more gasevolution was observed. The solution was poured into brine and theresulting suspension was filtered through celite. The filtrate wasdiluted with EtOAc and water, and the layers were separated. The organiclayer was dried over MgSO₄, filtered, and concentrated. The residue waspurified by flash chromatography (0-70-100% EtOAc/hexanes). Both of theundesired diastereomers were separated, affording an inseparable 1:1mixture of the title compounds (842 mg, 62%) as single diastereomers.Peak 1: LCMS calculated for C₁₇H₂₆ClN₄O₃S₂ (M+H)⁺: m/z=433.1; found433.1. Peak 2: LCMS calculated for C₁₇H₂₅ClFN₄O₃S₂ (M+H)⁺: m/z=451.1;found 451.1.

Step 4.(S)-4-(6-(1-aminoethyl)-4-chloropyrazolo[1,5-a]pyridin-7-yl)thiomorpholine1,1-dioxide hydrochloride &(S)-4-(6-(1-aminoethyl)-4-chloro-3-fluoropyrazolo[1,5-a]pyridin-7-yl)thiomorpholine1,1-dioxide hydrochloride

To a solution ofN—((S)-1-(4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridin-6-yl)ethyl)-2-methylpropane-2-sulfinamideandN—((S)-1-(4-chloro-7-(1,1-dioxidothiomorpholino)-3-fluoropyrazolo[1,5-a]pyridin-6-yl)ethyl)-2-methylpropane-2-sulfinamide(1:1 mixture, 842 mg, ˜1.945 mmol) in MeOH (10 ml) was added HCl (4.0Min dioxane) (10 mL, 40 mmol) and the reaction mixture was stirred atroom temperature for 0.5 h. LCMS indicated the reaction was complete,and the volatiles were removed in vacuo. The residue was used withoutpurification. Peak 1: LCMS calculated for C₁₃H₁₅ClN₃O₂S (M−NH₂)⁺:m/z=312.1; found 312.0. Peak 2: LCMS calculated for C₁₃H₁₄ClFN₃O₂S(M−NH₂)⁺: m/z=330.1; found 330.0.

Step 5.(S)-2-amino-N-(1-(4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate &(S)-2-amino-N-(1-(4-chloro-7-(1,1-dioxidothiomorpholino)-3-fluoropyrazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

To a vial containing(S)-4-(6-(1-aminoethyl)-4-chloropyrazolo[1,5-a]pyridin-7-yl)thiomorpholine1,1-dioxide hydrochloride and(S)-4-(6-(1-aminoethyl)-4-chloro-3-fluoropyrazolo[1,5-a]pyridin-7-yl)thiomorpholine1,1-dioxide hydrochloride (1:1 mixture, 710 mg, 1.944 mmol),2-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (649 mg, 2.333 mmol), and HATU (887 mg, 2.333 mmol) was added DMF(12 ml), followed by dropwise addition of DIPEA (1.018 ml, 5.83 mmol) atroom temp. After stirring for 0.5 h, the reaction was quenched withwater and extracted with EtOAc. The organic layer was washed with brine,dried over MgSO₄, and concentrated. The residue was dissolved in DCM(6.0 ml) and TFA (6 ml, 78 mmol) was added at room temp. After stirringfor 0.5 h, the volatiles were evaporated in vacuo and the products werepurified by prep HPLC (pH 2). Peak 1 (Example 57): ¹H NMR (600 MHz,DMSO) δ 8.92 (dd, J=6.7, 1.6 Hz, 1H), 8.57 (dd, J=4.5, 1.6 Hz, 1H), 8.14(d, J=2.3 Hz, 1H), 8.10 (d, J=6.9 Hz, 1H), 7.50 (s, 1H), 7.01 (dd,J=6.7, 4.5 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 5.73 (p, J=7.0 Hz, 1H),4.28-4.24 (m, 1H), 4.17-4.12 (m, 1H), 3.59-3.46 (m, 3H), 3.37-3.21 (m,3H), 1.56 (d, J=7.0 Hz, 3H). LCMS calculated for C₂₀H₂₂ClN₈O₃S (M+H)⁺:m/z=489.1; found 489.0. Peak 2 (Example 58): ¹H NMR (600 MHz, DMSO) δ8.92 (dd, J=6.7, 1.6 Hz, 1H), 8.57 (dd, J=4.5, 1.6 Hz, 1H), 8.26 (d,J=3.7 Hz, 1H), 8.09 (d, J=6.9 Hz, 1H), 7.46 (d, J=1.9 Hz, 1H), 7.02 (dd,J=6.7, 4.5 Hz, 1H), 5.68 (p, J=7.0 Hz, 1H), 4.22-4.15 (m, 1H), 4.13-4.05(m, 1H), 3.60-3.45 (m, 3H), 3.35 (d, J=13.3 Hz, 1H), 3.26 (m, 2H), 1.55(d, J=7.0 Hz, 3H). LCMS calculated for C20H2,C1FN803S (M+H)⁺: m/z=507.1;found 507.1.

Example 59.2-Amino-N-(1-(4-chloro-7-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. 1-(4-chloro-7-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)ethanone

A mixture of 1-(4,7-dichloropyrazolo[1,5-a]pyridin-6-yl)ethanone (19.0mg, 0.0829 mmol, from Example 56, Step 7),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (26 mg, 0.12mmol), tetrakis(triphenylphosphine)palladium(O) (10 mg, 0.008 mmol), andsodium carbonate (18 mg, 0.16 mmol) was taken up in 1,4-dioxane (2.5 mL,32 mmol) and water (0.5 mL, 30 mmol) and heated to 100° C. for 2 h. Thereaction mixture was cooled to room temperature, partitioned betweenEtOAc and water, and the layers were separated. The organic layer waswashed with brine, dried over MgSO₄, and concentrated. The residue waspurified by flash chromatography (0-100% EtOAc/hexanes) to afford thetitle compound as a white solid (16.4 mg, 73%). LCMS calculated forC₁₄H₁₁ClN₃O (M+H)⁺: m/z=272.1; found 272.1.

Step 2.2-amino-N-(1-(4-chloro-7-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

This compound was prepared according to the procedure described inExample 56, Step 9, starting from1-(4-chloro-7-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)ethanone insteadof1-(6-acetyl-4-chloropyrazolo[1,5-a]pyridin-7-yl)piperidine-4-carbonitrile.The residue was purified by preparative HPLC (pH 2) to afford the titlecompound (4.3 mg, 16%) as a white solid. LCMS calculated for C₂₁H₁₈ClN₈O(M+H)⁺: m/z=433.1; found 433.0.

Example 60.2-Amino-N-(1-(4-chloro-3-cyano-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. 6-acetyl-4,7-dichloropyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of 1-(4,7-dichloropyrazolo[1,5-a]pyridin-6-yl)ethan-1-one(110 mg, 0.480 mmol, from Example 56, Step 7) in acetonitrile (3.0 ml)was added chlorosulfonyl isocyanate (0.13 ml, 1.44 mmol) at roomtemperature. After stirring for 1 h, the reaction mixture was cooled to0° C. and DMF (0.11 ml, 1.44 mmol) was added dropwise. The ice bath wasremoved and the reaction mixture was stirred at room temperature for 0.5h. The reaction mixture was diluted with EtOAc and quenched with icechips, and the layers were separated. The aqueous layer was extractedwith EtOAc. The combined organic layers were washed with brine, driedover MgSO₄, filtered, and concentrated. The residue was purified byflash chromatography (0-30% EtOAc/hexanes) to afford the title compound(103 mg, 84%) as a light yellow solid. LCMS calculated for C₁₀H₆Cl₂N₃O(M+H)⁺: m/z=254.0; found 253.8.

Step 2.6-acetyl-4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of 6-acetyl-4,7-dichloropyrazolo[1,5-a]pyridine-3-carbonitrile(20 mg, 0.079 mmol), thiomorpholine 1,1-dioxide (21.3 mg, 0.157 mmol),and DIPEA (0.027 ml, 0.157 mmol) was heated to 140° C. in a microwavereactor for 1 h. LCMS indicated complete conversion to the desiredproduct. The reaction mixture was diluted with EtOAc, washed with waterand brine, dried over MgSO₄, and concentrated. The product was usedwithout purification. LCMS calculated for C₁₄H₁₄ClN₄O₃S (M+H)⁺:m/z=353.0; found 353.0.

Step 3.6-(1-aminoethyl)-4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridine-3-carbonitrilehydrochloride

This compound was prepared according to the procedure described inExamples 57-58, Steps 3-4, starting from6-acetyl-4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridine-3-carbonitrile,with the exception that the diastereomers from the reductive aminationstep were not separated. The product was used without purification. LCMScalculated for C₁₄H₁₄ClN₄O₂S (M−NH₂)⁺: m/z=337.1; found 337.1.

Step 4.2-amino-N-(1-(4-chloro-3-cyano-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

This compound was prepared according to the procedure described inExample 57-58, Step 5, starting from6-(1-aminoethyl)-4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridine-3-carbonitrilehydrochloride. The product was purified by preparative HPLC (pH 2) toafford the title compound as a white solid. LCMS calculated forC₂₁H₂₁ClN₉O₃S (M+H)⁺: m/z=514.1; found 514.1.

Example 61.2-Amino-N-(1-(4-chloro-3-cyano-7-((S)-3-hydroxypiperidin-1-yl)pyrazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1.(S)-6-acetyl-4-chloro-7-(3-hydroxypiperidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

This compound was prepared according to the procedure described inExample 60, Step 2, utilizing (S)-piperidin-3-ol instead ofthiomorpholine 1,1-dioxide. LCMS calculated for C₁₅H₁₆ClN₄O₂ (M+H)⁺:m/z=319.1; found 319.0.

Step 2.2-amino-N-(1-(4-chloro-3-cyano-7-((S)-3-hydroxypiperidin-1-yl)pyrazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate (mixture of diastereomers prepared)

This compound was prepared according to the procedure described inExample 56, Step 9, starting from(S)-6-acetyl-4-chloro-7-(3-hydroxypiperidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.The product was purified by preparative HPLC (pH 2). LCMS calculated forC₂₂H₂₃ClN₉O₂ (M+H)^(±): m/z=480.2; found 480.0.

Example 62.2-amino-N-(1-(8-chloro-5-cyclopentylimidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. 1-(8-chloro-5-cyclopentylimidazo[1,5-a]pyridin-6-yl)ethanone

To a suspension of copper cyanide (39 mg, 0.44 mmol) in THF (0.8 mL) andHMPA (0.2 mL) at −78° C. was added cyclopentylmagnesium bromide(2M/Et₂O, 0.22 mL, 0.44 mmol) dropwise.

After stirring at this temperature for 15 min, a solution of1-(5,8-dichloroimidazo[1,5-a]pyridin-6-yl)ethanone (20.0 mg, 0.0873mmol, from Example 130, Step 7) in THF (0.5 mL) was added dropwise, andthe reaction mixture was allowed to warm to room temperature overnight.The reaction was quenched with 1M HCl and extracted with EtOAc. Theorganic layer was washed with brine, dried over MgSO₄, and concentrated.The residue was purified by flash chromatography (0-40% EtOAc/hexanes)to afford the title compound (11 mg, 48%). LCMS calculated forC₁₄H₁₆ClN₂O (M+H)⁺: m/z=263.1; found 263.1.

Step 2.2-amino-N-(1-(8-chloro-5-cyclopentylimidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

This compound was prepared according to the procedure described inExample 56, Step 9, starting from1-(8-chloro-5-cyclopentylimidazo[1,5-a]pyridin-6-ypethanone. The productwas purified by preparative HPLC (pH 2) to afford the title compound asa white solid. ¹H NMR (600 MHz, DMSO) δ 8.92 (dd, J=6.7, 1.6 Hz, 1H),8.56 (dd, J=4.5, 1.6 Hz, 1H), 8.51 (s, 1H), 8.12 (d, J=6.8 Hz, 1H), 7.64(s, 1H), 7.17 (s, 1H), 7.01 (dd, J=6.7, 4.5 Hz, 1H), 5.45 (p, J=6.9 Hz,1H), 4.10 (p, J=6.0 Hz, 1H), 2.16-1.98 (m, 4H), 1.93-1.85 (m, 2H),1.84-1.79 (m, 2H), 1.54 (d, J=7.0 Hz, 3H). LCMS calculated forC₂₁H₂₃ClN₇O (M+H)⁺: m/z=424.2; found 424.2.

Example 63.2-Amino-N-(1-(4-chloro-7-phenyl-[1,2,3]triazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. methyl 5-chloro-2-phenylnicotinate

A solution of methyl 2,5-dichloronicotinate (10.7 g, 51.9 mmol, from WO2011/130342, Example 1, Step A, the disclosure of which is incorporatedherein in its entirety), phenylboronic acid (6.65 g, 54.5 mmol), andpotassium carbonate (15.6 g, 113 mmol) in water (50 mL) and 1,4-Dioxane(200 mL) was degassed with nitrogen (10 min). The reaction mixture wastreated with bis(triphenylphosphine)palladium(II) chloride (2 g, 2mmol), degassed with nitrogen (10 min), and heated at 80° C. for 3hours. The reaction mixture was diluted with EtOAc and water. Theaqueous layer was separated and extracted with EtOAc. The combinedorganic layers were washed with water and brine, dried with magnesiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography (O-40% EtOAc/hexanes) to afford the title compound (11.3g, 88%) as a yellow oil, which solidified upon standing. LCMS calculatedfor C₁₃H₁₁ClNO₂ (M+H)⁺: m/z=248.0; found 248.0.

Step 2. 5-chloro-3-(methoxycarbonyl)-2-phenylpyridine 1-oxide

Methyl 5-chloro-2-phenylnicotinate (400.0 mg, 1.615 mmol) was stirred inethaneperoxoic acid (14 mmol, 3 mL) at 90° C. for 1.5 h. The volatileswere removed in vacuo and the residue was purified by flashchromatography (0-100% EtOAc/hexanes) to afford the title compound (283mg, 66%) as a viscous oil. LCMS calculated for C₁₃H₁₁ClNO₃ (M+H)⁺:m/z=264.0; found 264.0.

Step 3. methyl 5,6-dichloro-2-phenylnicotinate

Methyl 5-chloro-2-phenylnicotinate 1-oxide (243.0 mg, 0.9216 mmol) wasstirred in phosphoryl chloride (32 mmol, 3 mL) at 90° C. for 1 h. Theblack reaction mixture was cooled to room temperature and the volatileswere evaporated. The residue was purified by flash chromatography (0-20%EtOAc/hexanes) to afford the title compound (193 mg, 74%) as a whitepowder. LCMS calculated for C₁₅H₁₃ClNO₂ (M+H)⁺: m/z=282.0; found 282.0.

Step 4. methyl 5-chloro-2-phenyl-6-vinylnicotinate

A mixture of methyl 5,6-dichloro-2-phenylnicotinate (54.0 mg, 0.191mmol), tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.01 mmol),pyridine—trivinylboroxin (1:1) (55 mg, 0.23 mmol), and potassiumcarbonate (79 mg, 0.57 mmol) in dioxane (2 mL) and water (0.5 mL) waspurged with N₂ for 5 minutes and heated to 100° C. for 1 h. The reactionmixture was diluted with EtOAc, washed with water and brine, dried overMgSO₄, filtered, and concentrated. The residue was purified by flashchromatography (0-20% EtOAc/hexanes) to afford the title compound (37mg, 71%) as a colorless oil. LCMS calculated for C₁₅H₁₃ClNO₂ (M+H)⁺:m/z=274.1; found 274.0.

Step 5. methyl 5-chloro-6-formyl-2-phenylnicotinate

To a solution of methyl 5-chloro-2-phenyl-6-vinylnicotinate (254 mg,0.928 mmol) in THF (4 mL) was added sodium periodate (0.60 g, 2.8 mmol),followed by osmium tetroxide (4%/H₂O, 60 μL, 0.009 mmol) and thereaction mixture was stirred at room temperature overnight. The reactionmixture was diluted with EtOAc and filtered. The organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was used without purification. LCMS calculated for C₁₄H₁₁ClNO₃(M+H)⁺: m/z=276.0; found 276.0.

Step 6. methyl 5-chloro-6-(hydrazonomethyl)-2-phenylnicotinate

To a solution of methyl 5-chloro-6-formyl-2-phenylnicotinate (254 mg,0.921 mmol) in methanol (120 mmol) was added hydrazine (58 μL, 1.8 mmol)and the reaction mixture was heated to 55° C. for 0.5 h. The reactionmixture was filtered and the volatiles were evaporated. The residue wasused without purification. LCMS calculated for C₁₄H₁₃ClN₃O₂ (M+H)⁺:m/z=290.1; found 290.0.

Step 7. 1-(4-chloro-7-phenyl-[1,2,3]triazolo[1,5-a]pyridin-6-yl)ethanone

To a solution of methyl 5-chloro-6-(hydrazonomethyl)-2-phenylnicotinate(267 mg, 0.922 mmol) in DCM (6 mL) was added iodobenzene diacetate (440mg, 1.4 mmol) and the reaction mixture was stirred at room temperaturefor 2 h. The volatiles were evaporated in vacuo and the residue waspurified by flash chromatography (0-25% EtOAc/hexanes) to afford thetitle compound (165 mg, 62% over 3 steps). LCMS calculated forC₁₄H₁₁ClN₃O₂ (M+H)⁺: m/z=288.1; found 288.0.

Step 8. 4-chloro-7-phenyl-[1,2,3]triazolo[1,5-a]pyridine-6-carboxylicacid

To a solution of methyl4-chloro-7-phenyl[1,2,3]triazolo[1,5-a]pyridine-6-carboxylate (165 mg,0.574 mmol) in methanol (74 mmol) was added 3.0 M sodium hydroxide inwater (1.91 mL, 5.74 mmol) and the reaction mixture was stirred at roomtemperature for 1 h. The volatiles were evaporated in vacuo and theresidue was treated with 1M HCl, forming a precipitate, which wassolubilized by addition of EtOAc. The solution was diluted withadditional EtOAc and 1M HCl, and the layers were separated. The organiclayer was washed with brine, dried over MgSO₄, filtered, andconcentrated, providing a white solid that was used withoutpurification. LCMS calculated for C₁₃H₉ClN₃O₂ (M+H)⁺: m/z=274.0; found274.0.

Step 9.4-chloro-N-methoxy-N-methyl-7-phenyl-f1,2,31triazolof1,5-alpyridine-6-carboxamide

To a solution of4-chloro-7-phenyl[1,2,3]triazolo[1,5-a]pyridine-6-carboxylic acid (157mg, 0.574 mmol), N,O-dimethylhydroxylamine hydrochloride (110 mg, 1.1mmol), and HATU (440 mg, 1.1 mmol) in DMF (4 mL) was addedN,N-diisopropylamine (0.40 mL, 2.9 mmol) and the reaction mixture wasstirred at room temperature overnight. After diluting with EtOAc, thereaction mixture was quenched with water and extracted with EtOAc. Theorganic layer was dried over MgSO₄, filtered, and concentrated. Theresidue was purified by flash chromatography (0-40% EtOAc/hexanes) toafford the title compound (127 mg, 70%). LCMS calculated forC₁₅H₁₄ClN₄O₂ (M+H)⁺: m/z=317.1; found 317.1.

Step 10.1-(4-chloro-7-phenyl-[1,2,3]triazolo[1,5-a]pyridin-6-yl)ethanone

To a solution of4-chloro-N-methoxy-N-methyl-7-phenyl[1,2,3]triazolo[1,5-a]pyridine-6-carboxamide(127 mg, 0.401 mmol) in THF (3 mL) at 0° C. was added methylmagnesiumbromide (3M/THF, 0.53 mL, 1.6 mmol) dropwise. After stirring for 1 h,the reaction was quenched with 1M HCl and warmed to room temperature.The reaction mixture was diluted with EtOAc and poured into saturatedaqueous NaHCO₃. The layers were separated and the organic layer wasdried over MgSO₄, filtered, and concentrated. The residue was purifiedby flash chromatography (0-25% EtOAc/hexanes) to afford the titlecompound (31 mg, 28%) as a white solid. LCMS calculated for C₁₄H₁₁ClN₃O(M+H)⁺: m/z=272.1; found 271.9.

Step 11.2-amino-N-(1-(4-chloro-7-phenyl-[1,2,3]triazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

This compound was prepared according to the procedure described inExample 56, Step 9, starting from1-(4-chloro-7-phenyl-[1,2,3]triazolo[1,5-a]pyridin-6-ypethanone. Theproduct was purified by preparative HPLC (pH 2). ¹H NMR (600 MHz, DMSO)δ 8.92 (dd, J=6.7, 1.6 Hz, 1H), 8.57 (dd, J=4.5, 1.6 Hz, 1H), 8.35 (s,1H), 8.15-8.10 (m, 1H), 7.83 (s, 1H), 7.70-7.57 (m, 4H), 7.56-7.46 (m,1H), 7.02 (dd, J=6.7, 4.5 Hz, 1H), 4.91 (p, J=6.9 Hz, 1H), 1.48 (d,J=7.0 Hz, 3H). LCMS calculated for C₂₁H₁₈ClN₈O (M+H)⁺: m/z=433.1; found433.1.

Example 64.2-Amino-N-{1-[7-(3-aminopropoxy)-4-chloro-1H-indazol-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidebis(trifluoroacetate)

Step 1. tert-Butyl[3-(6-acetyl-4-chloro-3-methyl-2-nitrophenoxy)propyl]carbamate

To a mixture of 1-(5-chloro-2-hydroxy-4-methyl-3-nitrophenypethanone(0.50 g, 2.2 mmol), tert-butyl (3-hydroxypropyl)carbamate (0.74 mL, 4.4mmol), and triphenylphosphine (1.3 g, 4.9 mmol) in tetrahydrofuran (5.0mL) at 0° C. was added dropwise diisopropyl azodicarboxylate (0.86 mL,4.4 mmol). The 0° C. bath was removed, and the reaction mixture wasstirred overnight. The reaction mixture was partioned between water andEtOAc. The organic layer was separated, washed with brine, dried oversodium sulfate, filtered, and concentrated. Purification via silica gelchromatography (5-40% EtOAc in hexanes) afforded the title compound 0.81g, 97%) as a white solid. LCMS for C₁₇H₂₃ClN₂NaO₆ (M+Na)⁺: calculatedm/z=409.1; found 409.1.

Step 2: tert-Butyl[3-(6-acetyl-2-amino-4-chloro-3-methylphenoxy)propyl]carbamate

To a solution of tert-butyl[3-(6-acetyl-4-chloro-3-methyl-2-nitrophenoxy)propyl]carbamate (760 mg,2.0 mmol) in methanol (10.0 mL) and acetic acid (2.4 mL) was added zinc(604.7 mg, 9.248 mmol). The reaction mixture was stirred rapidly for 1hour at room temperature. The reaction mixture was filtered throughcelite, and the filter cake was rinsed with MeOH. The filtrate wasconcentrated. The resulting residue was dissolved in EtOAc and washedwith sat. NaHCO₃ and then brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated to afford the title compound (0.75 g,106%) which was used without further purification. LCMS forC₁₇H₂₅ClN₂NaO₄ (M+Na)⁺: calculated m/z=379.1; found 379.1.

Step 3: teat-Butyl{3-[(6-acetyl-4-chloro-1H-indazol-7-yl)oxy]propyl}carbamate

To a solution of tert-butyl[3-(6-acetyl-2-amino-4-chloro-3-methylphenoxy)propyl]carbamate (750.0mg, 2.1 mmol) in acetic acid (10.0 mL) was added dropwise a solution ofsodium nitrite (140 mg, 2.1 mmol) in water (11 mL). The reaction mixturewas stirred at room temperature overnight. The reaction mixture wasdiluted with EtOAc, and the reaction was quenched with sat. NaHCO₃ untilthe aqueous layer reached pH 8. The organic layer was removed, and theaqueous layer was extracted with EtOAc. The combined organic layers weredried over Mg₂SO₄, filtered, and concentrated. Purification on silicagel column using EtOAc/hexane as the eluent gave the title compound(0.60 g, 78%). LCMS for C₁₇H₂₂ClN₃NaO₄ (M+Na)⁺: calculated m/z=390.1;found 390.1

Step 4: tert-Butyl(3-{[6-(1-aminoethyl)-4-chloro-1H-indazol-7-yl]oxy}propyl)carbamate

To a solution of tert-butyl{3-[(6-acetyl-4-chloro-1H-indazol-7-yl)oxy]propyl}carbamate (300 mg,0.82 mmol) in 2.0 M ammonia in ethanol (15 mL, 30. mmol) was addedtitanium tetraisopropoxide (0.72 mL, 2.4 mmol), and the reaction mixturewas heated at 60° C. for 5 hours. The reaction mixture was cooled toroom temperature and then 0° C., and sodium tetrahydroborate (92 mg, 2.4mmol) was added. The reaction mixture was stirred at 0° C. for 45 min.The mixture was quenched with 1 M NH₄OH (5.0 mL), filtered, and thesolid was washed with acetonitrile. Volatiles were removed in vacuo. Theresulting residue was dissolved in EtOAc and washed with water andbrine, sequentially. The organic layer dried over Na₂SO₄ andconcentrated to afford the title compound (0.30 g, 100%), which used inthe next step without purification. LCMS for C₁₇H₂₅ClN₄NaO₃ (M+Na)⁺:calculated m/z=391.2; found 391.1

Step 5: teat-Butyl[3-({[1-(7-{3-[(tert-butoxycarbonyl)amino]propoxy}-4-chloro-1H-indazol-6-yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]arbamate

To a flask containing2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (270 mg, 0.98 mmol), tert-butyl(3-{[6-(1-aminoethyl)-4-chloro-1H-indazol-7-yl]oxy}propyl)carbamate(0.30 g, 0.82 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (370 mg, 0.98 mmol) was added N,N-dimethylformamide(60 mL). N,N-diisopropylethylamine (1.4 mL, 8.2 mmol) was addeddropwise. After stirring for 5 min, the reaction mixture was partionedbetween EtOAc and sat. NaHCO₃. The organic layer was removed, dried overNa₂SO₄, and concentrated. The crude was purified on silica gel column togive the title compound (340 mg, 66%). LCMS for C₂₉H₃₇ClN₈NaO₆ (M+Na)⁺:calculated m/z=651.1; found 651.1

Step 6:2-Amino-N-{1-[7-(3-aminopropoxy)-4-chloro-1H-indazol-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidebis(trifluoroacetate)

A solution of tert-butyl[3-({[1-(7-{3-[(tert-butoxycarbonyl)amino]propoxy}-4-chloro-1H-indazol-6-yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate(76 mg, 0.12 mmol) in trifluoroacetic acid (0.5 mL) and dichloromethane(1.0 mL) was stirred for 1 h at room temperature. The reaction mixturewas concentrated to give the title compound (78 mg, 99%). LCMS forC₁₉H₂₂ClN₈O₂ (M+H)⁺: calculated m/z=429.1; found 429.1.

Examples 65-80

The following Examples 65-80 in Table 4 were prepared by the method ofExample 143. NMR data for representative compounds of Table 4 areprovided in Table 4a.

TABLE 4

Ex. LCMS No. Name NR₂ [M + H]⁺ 65 2-Amino-N-{1-[8-chloro-5-(4,4-difluoropiperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]- pyrimidine-3-carboxamidebistrifluoro- acetate

475.1 66 2-Amino-N-{1-[8-chloro-5-(4-fluoro-piperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-]pyrimidine-3- carboxamide bistrifluoroacetate

457.2 67 2-Amino-N-{1-[8-chloro-5-(3,3-difluoropiperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]- pyrimidine-3-carboxamide bistrifluoroacetate

475.2 68 2-Amino-N-{1-[8-chloro-5-(3,3-difluoropyrrolidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]- pyrimidine-3-carboxamidebistrifluoro-acetate

461.2 69 2-Amino-N-{1-[8-chloro-5-(4-methyl-piperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3- carboxamide bistrifluoroacetate

453.2 70 2-Amino-N-{1-[8-chloro-5-(2,2-dimethylpyrrolidin-1-yl)imidazo[1,5-a]-pyridin-6-yl]ethyl}pyrazolo[1,5-a]- pyrimidine-3-carboxamidebistrifluoro- acetate

453.2 71A 2-Amino-N-(1-{8-chloro-5-[(2R)-2-methylpyrrolidin-1-yl]imidazo[1,5-a]-pyridin-6-yl}ethyl)pyrazolo[1,5-a]- pyrimidine-3-carboxamidebistrifluoro- acetate

439.2 71B 2-Amino-N-(1-{8-chloro-5-[(2S)-2-methylpyrrolidin-1-yl]imidazo[1,5-a]-pyridin-6-yl}ethyl)pyrazolo[1,5-a]- pyrimidine-3-carboxamidebistrifluoro- acetate

439.2 72A 2-Amino-N-{1-[8-chloro-5-[(2R)-2-methylpiperidin-1-yl)imidazo[1,5-a]- pyridin-6-yl]ethyl}pyrazolo[1,5-a]-pyrimidine-3-carboxamide bistrifluoro- acetate

453.2 72B 2-Amino-N-{1-[8-chloro-5-[(2S)-2-methylpiperidin-1-yl)imidazo[1,5-a]- pyridin-6-yl]ethyl}pyrazolo[1,5-a]-pyrimidine-3-carboxamide bistrifluoro- acetate

453.2 73A 2-Amino-N-{1-[8-chloro-5-(3-fluoro-piperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3- carboxamide

457.2 73B 2-Amino-N-{1-[8-chloro-5-(3-fluoro-piperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3- carboxamide

457.2 73C-73D 2-Amino-N-{1-[8-chloro-5-(3-fluoro-piperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3- carboxamide

457.2 74 2-Amino-N-{1-[8-chloro-5-(3,3-dimethylpyrrolidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]- pyrimidine-3-carboxamidebistrifluoro- acetate

453.2 75A 2-Amino-N-(1-{8-chloro-5-[(3R)-3-fluoropyrrolidin-1-yl]imidazo[1,5-a]-pyridin-6-yl}ethyl)pyrazolo[1,5-a]- pyrimidine-3-carboxamidebistrifluoro- acetate

443.2 75B 2-Amino-N-(1-{8-chloro-5-[(3S)-3-fluoropyrrolidin-1-yl]imidazo[1,5-a]-pyridin-6-yl}ethyl)pyrazolo[1,5-a]- pyrimidine-3-carboxamidebistrifluoro- acetate

443.2 76A 2-Amino-N-{1-[8-chloro-5-(3-hydroxy-3-methylpiperidin-1-yl)imidazo[1,5-a]-pyridin-6-yl]ethyl}pyrazolo[1,5-a]- pyrimidine-3-carboxamide trifluoro-acetate

469.2 76B 2-Amino-N-{1-[8-chloro-5-(3-hydroxy-3-methylpiperidin-1-yl)imidazo[1,5-a]-pyridin-6-yl]ethyl}pyrazolo[1,5-a]- pyrimidine-3-carboxamide trifluoro-acetate

469.2 77A 2-Amino-N-{1-[8-chloro-5-(3-cyano-3-methylpiperidin-1-yl)imidazo[1,5-a]- pyridin-6-yl]ethyl}pyrazolo[1,5-a]-pyrimidine-3-carboxamide trifluoro- acetate

478.2 77B 2-Amino-N-{1-[8-chloro-5-(3-cyano-3-methylpiperidin-1-yl)imidazo[1,5-a]- pyridin-6-yl]ethyl}pyrazolo[1,5-a]-pyrimidine-3-carboxamide trifluoro- acetate

478.2 78A 2-Amino-N-(1-{8-chloro-5-[3-hydroxy-3-(trifluoromethyl)piperidin-1-yl]- imidazo[1,5-a]pyridin-6-yl}ethyl)-pyrazolo[1,5-a]pyrimidine-3-carbox- amide trifluoroacetate

523.2 78B 2-Amino-N-(1-{8-chloro-5-[3-hydroxy-3-(trifluoromethyl)piperidin-1-yl]- imidazo[1,5-a]pyridin-6-yl}ethyl)-pyrazolo[1,5-a]pyrimidine-3-carbox- amide trifluoroacetate

523.2 79 2-Amino-N-{1-[8-chloro-5-(2-oxo-3-oxa-1,8-diazaspiro[4.5]dec-8-yl)- imidazo[1,5-a]pyridin-6-yl]ethyl}-pyrazolo[1,5-a]pyrimidine-3-carbox- amide trifluoroacetate

510.2 80 2-Amino-N-{1-[8-chloro-5-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)- imidazo[1,5-a]pyridin-6-yl]ethyl}-pyrazolo[1,5-a]pyrimidine-3-carbox- amide trifluoroacetate

510.2

TABLE 4a Ex. No. ¹H NMR Data 73B ¹H NMR (DMSO) δ: 8.90 (d, J = 6.7 Hz,1H), 8.59-8.54 (m, 1H), 8.53 (s, 1H), 8.04 (d, J = 6.5 Hz, 1H), 7.46 (s,1H), 7.00 (m, 2H), 6.40 (d, J = 6.5 Hz, 2H), 5.40 (dt, J = 24.6, 6.8 Hz,1H), 5.02-4.75 (m, 1H), 3.64 (dd, J = 21.2, 10.9 Hz, 1H), 3.53-3.44 (m,2H), 3.44-3.33 (m, 2H), 1.97-1.88 (m, 2H), 1.56-1.47 (m, 3H), 1.30-1.13(m, 2H) 75A ¹H NMR (DMSO) δ: 8.91 (dt, J = 6.7, 1.9 Hz, 1H), 8.56 (dt, J= 3.5, 1.7 Hz, 1H), 8.48 (s, 1H), 8.09 (dd, J = 10.3, 6.9 Hz, 1H), 7.66(s, 1H), 7.13 (d, J = 11.9 Hz, 1H), 7.00 (ddd, J = 6.8, 4.5, 2.3 Hz,1H), 5.51 (m, 1H), 5.37 (dt, J = 22.4, 7.0 Hz, 1H), 3.85 (dd, J = 36.4,13.3 Hz, 2H), 3.73 (d, J = 16.3 Hz, 1H), 3.67-3.54 (m, 2H), 2.42-2.23(m, 1H), 1.52 (d, J = 7.0 Hz, 3H)

Example 81.2-Amino-N-(1-(4-chloro-7-(2-methoxyethoxy)-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. 1-(5-Chloro-2-(2-methoxyethoxy)-4-methyl-3-nitrophenyl)ethanone

1-Bromo-2-methoxyethane (62 μL, 0.65 mmol) was added to a mixture of1-(5-chloro-2-hydroxy-4-methyl-3-nitrophenyl)ethanone (0.10 g, 0.44mmol, from Biogene Organics, BG-C1031) and K₂CO₃ (0.12 g, 0.87 mmol) inDMF (1.0 mL). The reaction mixture was then heated at 60° C. for 1.5 h.An additional portion of the 1-bromo-2-methoxyethane (62 μL, 0.65 mmol)was added, and the reaction mixture was stirred for 1.5 days at 80° C.After cooling to room temperature, the reaction mixture was diluted withEtOAc (2 mL) and washed with water (2×2 mL) and then brine (2 mL). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated.Purification via silica gel chromatography (100% DCM) afforded the titlecompound as a red-orange oil (0.077 g, 61%). ¹H NMR (400 MHz, CDCl₃) δ7.72 (s, 1H), 4.18-4.02 (m, 2H), 3.67-3.55 (m, 2H), 3.36 (s, 3H), 2.65(s, 3H), 2.34 (s, 3H).

Step 2. 1-(3-Amino-5-chloro-2-(2-methoxyethoxy)-4-methylphenyl)ethanone

To a solution of1-(5-chloro-2-(2-methoxyethoxy)-4-methyl-3-nitrophenypethanone (76 mg,0.26 mmol) in MeOH (5.2 mL) and acetic acid (AcOH, 1.3 mL) was addedzinc powder (0.10 g, 1.6 mmol). The reaction mixture was stirred rapidlyfor 25 min at room temperature. The reaction mixture was filteredthrough Celite, rinsing with MeOH. The filtrate was concentrated. Theresulting residue was dissolved in EtOAc and washed with sat. NaHCO₃ andthen brine. The organic layer was dried over Na₂SO₄, filtered, andconcentrated to afford the title compound as a yellow-brown solid (69.7mg, >99%). LCMS for C₁₂H₁₇ClNO₃ (M+H)⁺: calculated m/z=258.1; found258.0.

Step 3. 1-(4-Chloro-7-(2-methoxyethoxy)-1H-indazol-6-yl)ethanone

The title compound was was synthesized according to an experimentalprocedure analogous to the synthesis of Example 1, Step 3, substituting1-(3-amino-5-chloro-2-(2-methoxyethoxy)-4-methylphenyl)ethanone for1-(3-amino-5-chloro-2-ethoxy-4-methylphenyl)ethanone. LCMS forC₁₂H₁₂ClN₂O₃ (M+H)⁺: calculated m/z=269.1; found 269.0.

Step 4.2-Amino-N-(1-(4-chloro-7-(2-methoxyethoxy)-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

To a solution of1-(4-chloro-7-(2-methoxyethoxy)-1H-indazol-6-yl)ethanone (10 mg, 0.037mmol) and racemic 2-methylpropane-2-sulfinamide (12 mg, 0.099 mmol) inTHF (0.090 mL) was added titanium(IV) ethoxide (0.02 mL, 0.07 mmol). Thereaction mixture was stirred at 70° C. in a sealed vial for 7 h. Thereaction mixture was then cooled to −44° C. L-Selectride (0.11 mL, 0.11mmol, 1.0 M in THF) was then added dropwise, and the reaction mixturewas warmed to room temperature while stirring overnight. The reactionmixture was then cooled to 0° C., and sodium borohydride (6 mg, 0.1mmol) was added. The reaction mixture was stirred overnight after comingto room temperature. The reaction mixture was again cooled to 0° C., andthe reaction was quenched with MeOH (0.1 mL). The mixture was warmed toroom temperature and diluted with EtOAC (0.25 mL). Brine (10 μL) wasthen added, and the resulting slurry was stirred for 5 min. The slurrywas filtered through Celite, and the filter cake was washed with EtOAc.The filtrate was concentrated. The resulting resulting residue wasdissolved in MeOH (1.1 mL), and HCl (0.05 mL, 0.2 mmol, 4.0 M in1,4-dioxane) was added dropwise while the reaction flask was in a roomtemperature water bath. The bath was removed, and after stirring 1 h atroom temperature, the reaction mixture was concentrated. To a mixture ofthe the resulting residue,2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (14 mg, 0.050 mmol, from J&W PharmLab, 68R0546), andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (21 mg, 0.055 mmol) in DMF was added dropwiseN,N-diisopropylethylamine (0.05 mL, 0.3 mmol). The reaction mixture wasstirred 2 h at room temperature. The reaction mixture was thenpartitioned between EtOAc and sat. NaHCO₃. The organic layer wasremoved, filtered through a plug of Na₂SO₄, and concentrated. Theresulting residue was dissolved in DCM (2.3 mL) and TFA (0.2 mL). Thereaction mixture was then stirred for 1 h. Purification via preparativeHPLC on a C-18 column (pH 2, 36-51% MeCN/0.1% TFA (aq) over 5 min, 60mL/min) afforded the title compound as a white solid (7.7 mg, 38%). ¹HNMR (600 MHz, d₆-DMSO) δ 13.53 (s, 1H), 8.91 (dd, J=6.7, 1.6 Hz, 1H),8.56 (dd, J=4.5, 1.6 Hz, 1H), 8.14 (d, J=7.3 Hz, 1H), 8.09 (d, J=1.3 Hz,1H), 7.11 (s, 1H), 7.00 (dd, J=6.7, 4.5 Hz, 1H), 6.44 (s, 2H), 5.69-5.40(m, 1H), 4.43-4.36 (m, 1H), 4.36-4.29 (m, 1H), 3.86-3.62 (m, 2H), 3.36(s, 3H), 1.51 (d, J=7.0 Hz, 3H). LCMS for C₁₉H₂₀ClN₇NaO₃ (M+Na)⁺:calculated m/z=452.1; found 452.1.

Example 82.2-Amino-N-(1-(4-chloro-7-methoxy-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The title compound was was synthesized according to an experimentalprocedure analogous to the synthesis of Example 81, Steps 2-4,substituting 1-(5-chloro-2-methoxy-4-methyl-3-nitrophenypethanone for1-[5-chloro-2-(2-methoxyethoxy)-4-methyl-3-nitrophenyl]ethanone in Step2. ¹H NMR (600 MHz, d₆-DMSO) δ 13.64 (br s, 1H), 8.91 (dd, J=6.7, 1.6Hz, 1H), 8.57 (dd, J=4.5, 1.7 Hz, 1H), 8.21 (d, J=7.7 Hz, 1H), 8.11 (s,1H), 7.12 (s, 1H), 7.00 (dd, J=6.7, 4.5 Hz, 1H), 6.45 (br s, 2H), 5.52(apparent p, J=7.0 Hz, 1H), 4.05 (s, 3H), 1.51 (d, J=7.0 Hz, 3H). LCMSfor C₁₇H₁₆ClN₇NaO₂ (M+Na)⁺: calculated m/z=408.1; found 408.1.

Example 83.2-Amino-N-(1-(4-chloro-7-(difluoromethoxy)-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. 1-(5-Chloro-2-(difluoromethoxy)-4-methyl-3-nitrophenyl)ethanone

To a mixture of 1-(5-chloro-2-hydroxy-4-methyl-3-nitrophenypethanone(50. mg, 0.22 mmol, from Biogene Organics, BG-C1031) in 1:1 MeCN/H₂O(2.2 mL) at −78° C. was added KOH (0.24 g, 4.4 mmol) and then diethyl[bromo(difluoro)methyl]phosphonate (80 μL, 0.4 mmol, from MatrixScientific, 007430). The reaction mixture was warmed to roomtemperature. After stirring for 30 min, the reaction mixture was cooledto −78° C., and an additional portion of diethyl[bromo(difluoro)methyl]phosphonate (80 μL, 0.4 mmol) was added. Thereaction mixture was stirred 30 min during which time it came to roomtemperature. The reaction mixture was then extracted with Et₂O (3×3 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification via silica gel chromatography (1-20% EtOAc inhexanes) afforded the title compound as a light yellow oil (26 mg, 43%).¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 6.55 (t, J=73.6 Hz, 1H), 2.61(s, 3H), 2.40 (s, 3H). ¹H NMR (376 MHz, CDCl₃) δ −81.80.

Step 2.2-Amino-N-(1-(4-chloro-7-(difluoromethoxy)-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The title compound was was synthesized according to experimentalprocedures analogous to Example 81, Steps 2-4, substituting1-(5-chloro-2-(difluoromethoxy)-4-methyl-3-nitrophenyl)ethanone for1-[5-chloro-2-(2-methoxyethoxy)-4-methyl-3-nitrophenyl]ethanone in Step2. LCMS for C₁₇H₁₅ClF₂N₇O₂ (M+H)⁺: calculated m/z=422.1; found 422.1.

Example 84.2-Amino-N-(1-(4-chloro-7-(2-hydroxyethoxy)-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1.1-(2-(2-(tert-Butyldimethylsilyloxy)ethoxy)-5-chloro-4-methyl-3-nitrophenyl)ethanone

Diisopropyl azodicarboxylate (0.26 mL, 1.3 mmol) was added dropwise to amixture of 1-(5-chloro-2-hydroxy-4-methyl-3-nitrophenyl)ethanone (0.15g, 0.65 mmol, from Biogene Organics, BG-C1031),2-{[tert-butyl(dimethypsilyl]oxy}ethanol (0.26 mL, 1.3 mmol), andtriphenylphosphine (0.39 g, 1.5 mmol) in THF at 0° C. The 0° C. bath wasremoved, and the reaction mixture was stirred for 6 h at roomtemperature. The reaction mixture was partitioned between water andEtOAc. The organic layer was separated, washed with brine, dried overNa₂SO₄, filtered, and concentrated. Purification via silica gelchromatography (1-12% EtOAc in hexanes) afforded the title compound as aclear oil (0.17 g, 67%). ¹H NMR (400 MHz, CDCl₃) δ 7.73 (s, 1H),4.03-3.97 (m, 2H), 3.90-3.83 (m, 2H), 2.68 (s, 3H), 2.34 (s, 3H), 0.88(s, 9H), 0.06 (s, 6H).

Step 2.1-(3-Amino-2-(2-(tert-butyldimethylsilyloxy)ethoxy)-5-chloro-4-methylphenyl)ethanone

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 81, Step 2 substituting1-(2-(2-(tert-butyldimethylsilyloxy)ethoxy)-5-chloro-4-methyl-3-nitrophenyl)ethanonefor 1-[5-chloro-2-(2-methoxyethoxy)-4-methyl-3-nitrophenyl]ethanone.LCMS for C₁₇H₂₉ClNO₃Si (M+H)⁺: calculated m/z=358.2; found 358.1.

Step 3.1-[7-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethoxy)-4-chloro-1H-indazol-6-yl]ethanone

To a solution of1-(3-amino-2-(2-(tert-butyldimethylsilyloxy)ethoxy)-5-chloro-4-methylphenyl)ethanone(0.13 g, 0.37 mmol) in AcOH (3.8 mL) was added dropwise a solution ofsodium nitrite (26 mg, 0.38 mmol) in H₂O (1.9 mL). The reaction mixturewas stirred at room temperature for 1.5 h and then concentrated. Theresulting orange oil was dissolved in DCM, and the resulting organicsolution was washed with sat. NaHCO₃ and then brine. The organic layerwas dried over Mg₂SO₄, filtered, and concentrated. Purification viasilica gel chromatography (5-40% EtOAc in hexanes [1% DCM]) afforded thetitle compound as a yellow orange solid (0.070 g, 52%). LCMS forC₁₇H₂₆ClN₂O₃Si (M+H)⁺: calculated m/z=369.1; found 369.1.

Step 4.1-[7-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethoxy)-4-chloro-1H-indazol-6-yl]ethanamine

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 23, Step 2 substituting1-[7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-4-chloro-1H-indazol-6-yl]ethanonefor 1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethanone LCMS forC₁₇H₂₆ClN₂O₂Si (M−NH₂)⁺: calculated m/z=353.1; found 353.1.

Step 5.2-Amino-N-(1-(4-chloro-7-(2-hydroxyethoxy)-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

To a mixture of1-[7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-4-chloro-1H-indazol-6-yl]ethanamine,2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (11 mg, 0.039 mmol, from J&W PharmLab, 68R0546), andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (16 mg, 0.043 mmol) in DMF (0.82 mL) was addeddropwise N,N-diisopropylethylamine (30 μL, 0.1 mmol). The reactionmixture was stirred overnight at room temperature. The reaction mixturewas then partitioned between EtOAc and sat. NaHCO₃. The organic layerwas removed, dried over Na₂SO₄, filtered, and concentrated. Theresulting residue was dissolved in MeOH (2.2 mL), and conc. HCl (0.15mL) was added. The reaction mixture was stirred at room temperature for1 h and then concentrated. The resulting residue was dissolved in DCM(1.8 mL) and TFA (0.2 mL). The reaction mixture was stirred for 1 h andthen concentrated. Purification via preparative HPLC on a C-18 column(pH 2, 26-46% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded thetitle compound as a white to tan solid (6.7 mg). LCMS for C₁₈H₁₉ClN₇O₃(M+H)⁺: calculated m/z=416.1; found 416.0.

Example 85.2-Amino-N-(1-(4-chloro-7-(2,3-dihydroxypropoxy)-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1.1-(5-Chloro-2((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-3-nitrophenyl)ethanone

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 84, Step 1 substituting2,2-dimethyl-1,3-dioxolane-4-methanol for2-{[tert-butyl(dimethyl)silyl]oxy}ethanol. ¹H NMR (400 MHz, CDCl₃) δ7.73 (s, 1H), 4.38 (apparent p, J=5.8 Hz, 1H), 4.10 (dd, J=8.6, 6.6 Hz,1H), 4.02-3.88 (m, 2H), 3.78 (dd, J=8.6, 5.9 Hz, 1H), 2.66 (s, 3H), 2.35(s, 3H), 1.41 (s, 3H), 1.37 (s, 3H). LCMS for C₁₅H₁₉ClNO₆ (M+H)⁺:calculated m/z=344.1; found 344.0.

Step 2.1-(3-Amino-5-chloro-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methylphenyl)ethanone

The title compound was was synthesized according to an experimentalprocedure analogous to the synthesis of Example 81, Step 2 substituting1-(5-chloro-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-3-nitrophenypethanonefor 1-[5-chloro-2-(2-methoxyethoxy)-4-methyl-3-nitrophenyl]ethanone.LCMS for C₁₅H₂₀ClNNaO₄ (M+Na)⁺: calculated m/z=336.1; found 336.0.

Step 3.1-(4-Chloro-7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1H-indazol-6-yl)ethanone

The title compound was was synthesized according to an experimentalprocedure analogous to the synthesis of Example 84, Step 3 substituting1-(3-amino-5-chloro-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methylphenyl)ethanonefor 1-[3-amino-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-5-chloro-4-methylphenyl]ethanoneLCMS for C₁₅H₁₈ClN₂O₄ (M+H)⁺: calculated m/z=325.1; found 325.0.

Step 4. 3-(6-(1-Aminoethyl)-4-chloro-1H-indazol-7-yloxy)propane-1,2-diolhydrochloride

To a solution of1-(4-chloro-7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1H-indazol-6-yl)ethanone(61 mg, 0.19 mmol) in 2.0 M NH₃ in EtOH (3.5 mL, 7.0 mmol) was addedtitanium(IV) isopropoxide (0.16 mL, 0.55 mmol), and the reaction mixturewas heated at 60° C. for 2 h. The reaction mixture was cooled to roomtemperature and then 0° C. NaBH₄ (21 mg, 0.55 mmol) was added, and thereaction mixture was stirred at 0° C. for 30 min. The reaction wasquenched with 1 M NH₄OH (1 mL) and diluted with MeCN. The resultingsuspension was stirred at room temperature for 5 min. The mixture wasthen filtered through Celite, and the filter cake was washed with MeCN.Volatiles were removed in vacuo. The resulting residue was dissolved inacetone (0.60 mL), and 1.0 M HCl (0.18 mL, 0.18 mmol) was added. Thereaction mixture was stirred at room temperature for 1.5 h. Anadditional portion of 1.0 M HCl (0.18 mL, 0.18 mmol) was added, and thereaction mixture was heated at 50° C. for 2 h. The reaction mixture wasconcentrated. The resulting residue was dissolved in 4.0 M HCl in1,4-dioxane (4 mL, 20 mmol) while the reaction flask was in a roomtemperature water bath. H₂O (14 μL, 0.75 mmol) was added, and afterremoval of the water bath, the reaction mixture was stirred at roomtemperature for 45 min. MeOH (1 mL, 20 mmol) was added, and the thereaction mixture was stirred at room temperature for 1.5 h. The reactionmixture was concentrated, and the product was used without purification(theoretical yield assumed). LCMS for C₁₂H₁₆ClN₃NaO₃ (M+Na)⁺: calculatedm/z=308.1; found 308.0.

Step 5. tert-Butyl1-(4-chloro-7-(2,3-dihydroxypropoxy)-1H-indazol-6-yl)ethylcarbamate

Triethylamine (50 μL, 0.36 mmol) was added to a mixture of3-(6-(1-aminoethyl)-4-chloro-1H-indazol-7-yloxy)propane-1,2-diolhydrochloride (0.061 g, 0.19 mmol) and di-tert-butyl dicarbonate (64 μL,0.28 mmol) in 1,4-dioxane (1.2 mL)/H₂O (58 4). The reaction mixture wasstirred at room temperature for 1.5 h. DCM (1.0 mL, 16 mmol) was added,and the reaction mixture was stirred for an additional 2 h. Anadditional portion of di-tert-butyl dicarbonate (64 μL, 0.28 mmol) andtriethylamine (50 μL, 0.36 mmol) were added, and the reaction mixturewas stirred at room temperature overnight. The reaction mixture wasconcentrated. Purification via silica gel chromatography (1-15% MeOH inDCM) afforded the title compound (25 mg). LCMS for C₁₇H₂₄ClN₃NaO₅(M+Na)⁺: calculated m/z=408.1; found 408.0.

Step 6. 3-(6-(1-Aminoethyl)-4-chloro-1H-indazol-7-yloxy)propane-1,2-dioltrifluoroacetate

tert-Butyl1-(4-chloro-7-(2,3-dihydroxypropoxy)-1H-indazol-6-yl)ethylcarbamate(12.5 mg, 0.0324 mmol) was dissolved in DCM (2.0 mL) and TFA (0.2 mL).After stirring at room temperature for 1 h, the reaction mixture wasthen concentrated to afford the title compound. The product was usedwithout purification (theoretical yield assumed). LCMS forC₁₂H₁₆ClN₃NaO₃ (M+Na)⁺: calculated m/z=308.1; found 308.0.

Step 7.2-Amino-N-(1-(4-chloro-7-(2,3-dihydroxypropoxy)-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

To a mixture of3-(6-(1-aminoethyl)-4-chloro-1H-indazol-7-yloxy)propane-1,2-dioltrifluoroacetate (0.0130 g, 0.0324 mmol),2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (12 mg, 0.043 mmol), andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (18 mg, 0.047 mmol) in DMF (0.9 mL) was addeddropwise N,N-diisopropylethylamine (40 uL, 0.2 mmol). The reactionmixture was stirred 1 h at room temperature. The reaction mixture wasthen partitioned between EtOAc and sat. NaHCO₃. The organic layer wasremoved, filtered through a plug of Na₂SO₄, and concentrated. Theresulting residue was dissolved in DCM (2 mL) and TFA (0.2 mL). Thereaction mixture was then stirred for 1 h and then concentrated.Purification via preparative HPLC on a C-18 column (pH 2, 25-45%MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded the title compound awhite solid (4 mg). LCMS for C₁₉H₂₀ClN₇NaO₄ (M+Na)⁺: calculatedm/z=468.1; found 468.1.

Example 86.2-Amino-N-(1-(4-chloro-3-cyano-7-ethoxy-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. 1-(4-chloro-7-ethoxy-3-iodo-1H-indazol-6-yl)ethanone

To a solution 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanone (0.266 g,1.11 mmol, from Example 1, Step 3) in DMF (5 mL) was addedN-iodosuccinimide (0.29 g, 1.3 mmol). After stirring overnight at roomtemperature, the reaction mixture was diluted with sat. NaHCO₃ andextracted with EtOAc. The organic layer was washed with saturated sodiumthiosulfate, dried over Na₂SO₄, and concentrated in vacuo. The crudeproduct was passed through a plug of silica gel eluting with 1:1DCM/EtOAc. The filtrate was concentrated, taken up into a mixture of DCMand hexanes, and concentrated to afford the title compound as a tansolid (0.175 g, 43%). ¹H NMR (400 MHz, d₆-DMSO) δ 7.32 (s, 1H), 4.24 (brs, 2H), 2.64 (s, 3H), 1.39 (t, J=7.0 Hz, 3H). LCMS for C₁₁H₁₁ClIN₂O₂(M+H)⁺: calculated m/z=365.0; found 364.8.

Step 2. Methyl 6-acetyl-4-chloro-7-ethoxy-1H-indazole-3-carboxylate

A mixture of 1-(4-chloro-7-ethoxy-3-iodo-1H-indazol-6-yl)ethanone (50mg, 0.14 mmol) and triethylamine (53 μL, 0.38 mmol) in 4:1 DMF/MeOH (2.5mL) was degassed with N₂ for 5 min.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (6 mg, 0.007 mmol) was added, and carbon monoxidewas bubbled through the reaction mixture for 10 min. The reactionmixture was then heated at 90° C. in sealed vial overnight. The reactionmixture was concentrated. Purification via silica gel chromatography(1-40% EtOAc/hexanes) afforded the title compound as a brown solid. LCMSfor C₁₃H₁₄ClN₂O₄ (M+H)⁺: calculated m/z=297.1; found 297.0.

Step 3. 6-Acetyl-4-chloro-7-ethoxy-1H-indazole-3-carboxylic acid

A solution of methyl6-acetyl-4-chloro-7-ethoxy-1H-indazole-3-carboxylate (53 mg, 0.18 mmol)in a mixture of THF (1.8 mL), MeOH (1.8 mL), and 1.0 M NaOH (1.8 mL, 1.8mmol) was heated at 65° C. for 4 h. After cooling to room temperature,the reaction mixture was concentrated by approximately half and thendiluted with EtOAc. 1M HCl was added and the layers were separated. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered, andconcentrated, providing the title compound as a tan solid (39 mg, 77%).LCMS for C₁₂H₁₂ClN₂O₄ (M+H)⁺: calculated m/z=283.0; found 283.1.

Step 4. 6-Acetyl-4-chloro-7-ethoxy-1H-indazole-3-carboxamide

To a mixture of 6-acetyl-4-chloro-7-ethoxy-1H-indazole-3-carboxylic acid(39 mg, 0.14 mmol), NH₄Cl (16 mg, 0.30 mmol), andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.10 g, 0.28 mmol) in DMF (1.7 mL) was addedN,N-diisopropylethylamine (0.12 mL, 0.69 mmol) at room temperature.After stirring 1.5 h, the reaction mixture was partitioned between EtOAcand sat. NaHCO₃. The layers were separated, and the organic layer wasdried over Na₂SO₄, filtered, and concentrated to afford a brown solid.This crude product was used without purification (theoretical yieldassumed). LCMS for C₁₂H₁₃ClN₃O₃ (M+H)⁺: calculated m/z=282.1; found281.9.

Step 5. 6-Acetyl-4-chloro-7-ethoxy-1H-indazole-3-carbonitrile

To a suspension of 6-acetyl-4-chloro-7-ethoxy-1H-indazole-3-carboxamide(0.039 g, 0.14 mmol) in DCM (3.9 mL) at 0° C. was added triethylamine(58 μL, 0.42 mmol). Trifluoromethanesulfonic anhydride in DCM (0.42 mL,0.42 mmol, 1.0 M) was then added dropwise. After the addition wascomplete, the reaction mixture was stirred at room temperature for 1 h.The reaction vial was placed in a room temperature water bath, and thereaction was quenched with saturated NaHCO₃. The organic layer wasremoved, and the aqueous layer was extracted with DCM (2×). The combinedorganic layers were dried over MgSO₄, filtered, and concentrated.Purification by silica gel chromatography (15-50% EtOAc/hexanes)afforded the title compound a light brown solid (6.7 mg, 18%). LCMS forC₁₂H₁₁ClN₃O₂ (M+H)⁺: calculated m/z=264.1; found 264.0.

Step 6. 6-(1-Aminoethyl)-4-chloro-7-ethoxy-1H-indazole-3-carbonitrile

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 23, Step 2 substituting6-acetyl-4-chloro-7-ethoxy-1H-indazole-3-carbonitrile for1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-ypethanone. LCMS forC₁₂H₁₁ClN₃O (M−NH₂)⁺: calculated m/z=248.1; found 248.0.

Step 7.2-Amino-N-(1-(4-chloro-3-cyano-7-ethoxy-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The title compound was was synthesized according to an experimentalprocedure analogous to the synthesis of Example 85, Step 7 substituting6-(1-aminoethyl)-4-chloro-7-ethoxy-1H-indazole-3-carbonitrile for3-(6-(1-aminoethyl)-4-chloro-1H-indazol-7-yloxy)propane-1,2-dioltrifluoroacetate. ¹H NMR (400 MHz, CD₃OD) δ 8.70 (dd, J=6.8, 1.6 Hz,1H), 8.55 (dd, J=4.5, 1.6 Hz, 1H), 8.47 (d, J=7.5 Hz, 1H), 7.35 (s, 1H),6.98 (dd, J=6.8, 4.5 Hz, 1H), 5.82-5.51 (m, 1H), 4.57 (s, 1H), 4.43-4.20(m, 1H), 1.60 (d, J=7.0 Hz, 3H), 1.55 (t, J=7.0 Hz, 3H). LCMS forC₁₉H₁₈ClN₈O₂ (M+H)⁺: calculated m/z=425.1; found 425.1.

Examples 87-89

The following Examples 87-89 in Table 5 were prepared by the method ofExample 143.

TABLE 5

Ex. LCMS No. Name NR₂ [M + H]⁺ 87 2-Amino-N-(1-(8-chloro-5-(4-hydroxy-4-methylpiperidin-1-yl)imidazo[1,5-a]- pyridin-6-yl)ethyl)pyrazolo[1,5-a]-pyrimidine-3-carboxamide trifluoroacetate

469.1 88 2-Amino-N-(1-(8-chloro-5-(4-cyano-4-methylpiperidin-1-yl)imidazo[1,5-a]- pyridin-6-yl)ethyl)pyrazolo[1,5-a]-pyrimidine-3-carboxamide trifluoroacetate

478.2 89 2-Amino-N-(1-(8-chloro-5-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)imidazo-[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]- pyrimidine-3-carboxamidetrifluoroacetate

523.1

Examples 90A-90B.2-Amino-N-{1-[4-chloro-7-(3-hydroxypyrrolidin-1-yl)-2H-indazol-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidebis(trifluoroacetate)

Step 1. 1-(3-Amino-5-chloro-2-methoxy-4-methylphenyl)ethanone

A solution of 1-(5-chloro-2-methoxy-4-methyl-3-nitrophenyl)ethanone(15.0 g, 61.6 mmol) [Oakwood, 019298] in methanol (1.20 L) and aceticacid (310 mL) was treated with zinc (24.2 g, 369 mmol) and stirred at20° C. for 15 min. The reaction mixture was decanted to leave behind thezinc. The solution was concentrated to a light brown solid that wasazeotroped with toluene (2×). The solid was diluted with methanol andthe insoluble white solid was filtered. The filtrate was concentrated,rediluted with ethyl acetate, and washed with water and brine. Theorganic layer was separated, dried with magnesium sulfate, filtered, andconcentrated to give the desired product (13.3 g, 101%) as a brown solidthat was used without further purification. LCMS for C₁₀H₁₃ClNO₂ (M+H)⁺:m/z=214.1; Found: 214.1.

Step 2. 1-(4-Chloro-7-methoxy-1H-indazol-6-yl)ethanone

A solution of 1-(3-amino-5-chloro-2-methoxy-4-methylphenyl)ethanone(13.2 g, 61.6 mmol) in acetic acid (300 mL) was treated with amylnitrite (9.1 mL, 68 mmol) dropwise and stirred at 110° C. for 30 min.The reaction mixture was concentrated and the resulting residue wasazeotroped with toluene (2×). The crude solid was diluted with diethylether and the heterogenous mixture was filtered to give the desiredproduct (9.95 g, 72%) as an orange-brown solid that was used withoutfurther purification. LCMS for C₁₀H₁₀ClN₂O₂ (M+H)⁺: m/z=225.0; Found:225.1.

Step 3. 1-(4-Chloro-7-hydroxy-1H-indazol-6-yl)ethanone

A solution of 1-(4-chloro-7-methoxy-1H-indazol-6-yl)ethanone (11.4 g,50.6 mmol) in hydrogen bromide (57.2 mL, 506 mmol) in a round bottomflask equipped with a condenser was stirred at 80° C. for 15 h. Thereaction mixture was quenched with ice and diluted with water. The solidthat precipitated was filtered and washed with water to give the desiredproduct (9.21 g, 87%) as a brown solid that was used without furtherpurification. LCMS for C₉H₈ClN₂O₂ (M+H)⁺: m/z=211.0; Found: 211.0.

Step 4. 6-Acetyl-4-chloro-1H-indazol-7-yl trifluoromethanesulfonate

A solution of 1-(4-chloro-7-hydroxy-1H-indazol-6-yl)ethanone (1.00 g,4.75 mmol) in tetrahydrofuran (40.0 mL) was treated with triethylamine(2.3 mL, 17 mmol), cooled to −78° C., treated with a solution of 1.0 Mtrifluoromethanesulfonic anhydride in dichloromethane (10.0 mL), andstirred at −78° C. for 1 h. The reaction mixture was diluted with ethylacetate and washed with saturated sodium bicarbonate. The organic layerwas separated, dried with magnesium sulfate, filtered, and concentratedto give a black oil. Purification by flash column chromatography usingethyl acetate in hexanes (0%-20%) gave the desired product (912 mg, 56%)as a brown solid. LCMS for C₁₀H₇ClF₃N₂O₄S (M+H)⁺: m/z=343.0; Found:342.9.

Step 5.6-Acetyl-4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-7-yltrifluoromethanesulfonate

A stirred solution of6-acetyl-4-chloro-1H-indazol-7-yltrifluoromethanesulfonate (0.8940 g,2.609 mmol) and N-cyclohexyl-N-methyl-cyclohexanamine (1.00 mL, 4.70mmol) in tetrahydrofuran (25.5 mL) at −78° C. was treated with[β-(trimethylsilypethoxy]methyl chloride (0.785 mL, 4.44 mmol) dropwise.The reaction mixture was warmed slowly to room temperature and wasstirred overnight. The reaction mixture was cooled to 0° C., quenchedwith water (100 mL), and extracted with ethyl acetate (100 mL). Theorganic layer was separated, washed with brine (40 mL), dried oversodium sulfate, filtered and concentrated to give a yellow oil.Purification by flash column chromatography using diethyl ether inhexanes (0%-30%) gave two separate isomers. The second peak that elutedwas the desired product (594 mg, 48%). LCMS for C₁₆H₂₀ClF₃N₂O₅SSiNa(M+Na)⁺: m/z=495.0; Found: 495.0.

Step 6.1-(4-Chloro-7-(3-hydroxypyrrohdin-1-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-6-yl)ethanone

A stirred suspension of6-acetyl-4-chloro-2-{[2-(trimethylsilypethoxy]methyl}-2H-indazol-7-yltrifluoromethanesulfonate (0.0687 g, 0.145 mmol) and sodium bicarbonate(0.0488 g, 0.581 mmol) in acetonitrile (0.578 mL) was treated with asolution of 3-pyrrolidinol (0.0316 g, 0.363 mmol) in acetonitrile (1.02mL). The suspension was stirred at ambient temperature for 2 h and at50° C. for 15 min. The reaction mixture was poured into a saturatedsodium bicarbonate solution (15 mL) and extracted with ethyl acetate (30mL). The organic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated to give a yellow residue. Purification byflash column chromatography using ethyl acetate in hexanes (0%-80%) gavethe desired product (56 mg, 94%) as a green yellow foam. LCMS forC₁₉H₂₉ClN₃O₃Si (M+H)⁺: m/z=410.2; Found: 410.1.

Step 7.1-(6-(1-Aminoethyl)-4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-7-yl)pyrrohdin-3-ol

A solution of1-(4-chloro-7-(3-hydroxypyrrolidin-1-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-6-yl)ethanone(56.4 mg, 0.138 mmol) in 2.0 M ammonia in ethanol (2.92 mL, 5.83 mmol)was treated with titanium tetraisopropoxide (102 μL, 0.344 mmol) andheated in a sealed tube at 60° C. for 14 h. The reaction mixture wascooled to 0° C., treated with sodium tetrahydroborate (13.0 mg, 0.344mmol), stirred at 0° C. for 30 mins, and at room temperature for 30 min.The reaction mixture was quenched with a few drops of water, filteredover Celite, and the Celite was washed with acetonitrile. The filtratewas concentrated to a residue, diluted with saturated sodiumbicarbonate, and extracted with dichloromethane (2×20 mL). The combinedorganic extracts were dried over sodium sulfate, filtered, andconcentrated to give the desired product (55 mg, 96%) as a tan foam thatwas used without further purification. LCMS for C₁₉H₃₂ClN₄O₂Si (M+H)⁺:m/z=411.2; Found: 411.2.

Step 8. teat-Butyl[3-({[1-(4-chloro-7-(3-hydroxypyrrolidin-1-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-6-yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate

The desired compound was prepared according to the procedure of Example1, step 6, using1-(6-(1-aminoethyl)-4-chloro-2-{[2-(trimethylsilypethoxy]methyl}-2H-indazol-7-yl)pyrrolidin-3-olas the starting material. LCMS for C₃₁H₄₄ClN₈O₅Si (M+H)⁺: m/z=671.3;Found: 671.3.

Step 9.2-Amino-N-{1-[4-chloro-7-(3-hydroxypyrrolidin-1-yl)-2H-indazol-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidebis(trifluoroacetate)

A solution of teat-butyl[3-({[1-(4-chloro-7-(3-hydroxypyrrolidin-1-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-6-yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate (21.3mg, 0.0317 mmol) in 4.0 M hydrogen chloride in dioxane (1.0 mL) andmethanol (0.5 mL) was stirred for 2 h. The volatiles were evaporated andthe crude residue was purified by preparative LCMS (XBridge C18 Column,eluting with a gradient of acetonitrile in water with 0.1%trifluoroacetic acid, at flow rate of 60 mL/min) to give two sets ofdiastereoisomers with each set containing mixtures of enantiomers. Thefirst peak that eluted (Example 90A, 5.5 mg, 26%) and the second peakthat eluted (Example 90B, 6.1 mg, 29%) were both white solids. Example90A: ¹H NMR (400 MHz, DMSO) δ 13.22 (s, 1H), 8.89 (dd, J=6.7, 1.4 Hz,1H), 8.71 (s, 1H), 8.54 (dd, J=4.5, 1.4 Hz, 1H), 8.26 (d, J=8.0 Hz, 1H),8.11 (s, 1H), 7.12 (s, 1H), 6.98 (dd, J=6.7, 4.5 Hz, 1H), 6.48 (s, 2H),5.74-5.56 (m, 1H), 4.63-4.44 (m, 1H), 3.36-3.24 (m, 1H), 3.21-3.10 (m,1H), 3.05 (d, J=10.7 Hz, 1H), 2.24-2.07 (m, 1H), 2.01-1.92 (m, 1H),1.60-1.40 (m, 3H). LCMS for C₂₀H₂₂ClN₈O₂ (M+H)⁺: m/z=441.2; Found:441.1. Example 90B: ¹H NMR (400 MHz, DMSO) δ 13.22 (s, 1H), 8.90 (dd,J=6.7, 1.3 Hz, 1H), 8.78-8.64 (m, 1H), 8.54 (dd, 1H), 8.32 (d, J=7.9 Hz,1H), 8.11 (s, 1H), 7.11 (s, 1H), 6.99 (dd, J=6.6, 4.6 Hz, 1H), 5.78-5.59(m, 1H), 4.52 (s, 1H), 3.31-3.18 (m, 1H), 3.11 (d, J=10.6 Hz, 1H),2.26-2.09 (m, 1H), 2.09-1.93 (m, 1H), 1.50 (d, J=6.9 Hz, 3H). LCMS forC₂₀H₂₂ClN₈O₂ (M+H)⁺: m/z=441.2; Found: 441.1.

Examples 91-94

The following Examples 91-94 of Table 6 were synthesized according tothe procedure of Examples 90A-90B. NMR data for the compounds of Table 6are provided in Table 6a.

TABLE 6

Ex. No. Name R LCMS 91 2-Amino-N-{1-[4-chloro-7-(3-methoxy-pyrrolidin-1-yl)-2H-indazol-6-yl]ethyl}-pyrazolo[1,5-a]pyrimidine-3-carbox- amide bis(trifluoroacetate)

for C₂₁H₂₄ClN₈O₂ (M + H)⁺: m/z = 455.2; Found: 455.1 922-Amino-N-[1-(4-chloro-7-{3-[(methyl-amino)sulfonyl]pyrrolidin-1-yl}-2H- indazol-6-yl)ethyl]pyrazolo[1,5-a]-pyrimidine-3-carboxamide

for C₂₁H₂₅ClN₉O₃S (M + H)⁺: m/z = 518.1; Found: 518.2 932-Amino-N-[1-(4-chloro-7-{4-[(dimeth-ylamino)sulfonyl]piperidin-1-yl}-2H- indazol-6-yl)ethyl]pyrazolo[1,5-a]-pyrimidine-3-carboxamide

for C₂₃H₂₉ClN₉O₃S (M + H)⁺: m/z = 546.2; Found: 546.3 942-Amino-N-{1-[4-chloro-7-(1,1-dioxido-thiomorpholin-4-yl)-2H-indazol-6-yl]- ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate

for C₂₀H₂₂ClN₈O₃S (M + H)⁺: m/z = 489.1; Found: 489.1

TABLE 6a Ex. No. ¹H NMR Data 91 ¹H NMR (400 MHz, DMSO) δ 13.05 (s, 1H),8.90 (dd, J = 6.7, 1.5 Hz, 1H), 8.55 (dd, J = 4.5, 1.5 Hz, 1H), 8.19 (d,J = 7.7 Hz, 1H), 8.11 (s, 1H), 7.12 (s, 1H), 6.99 (dd, J = 6.7, 4.5 Hz,1H), 6.42 (s, 2H), 5.78-5.48 (m, 1H), 4.35-4.11 (m, 1H), 3.31 (s, 3H),3.21-3.07 (m, 2H), 2.32-2.18 (m, 1H), 2.14-1.92 (m, 1H), 1.49 (d, J =6.9 Hz, 3H). 92 ¹H NMR (400 MHz, DMSO) δ 13.22 (s, 0.5H), 8.90 (d, J =6.4 Hz, 1H), 8.68-8.47 (m, 1H), 8.29-8.03 (m, 2H), 7.13 (s, 2H),7.04-6.90 (m, 1H), 6.53-6.30 (m, 2H), 5.85- 5.66 (m, 0.5H), 5.66-5.51(m, 0.5H), 4.33-4.12 (m, 1H), 3.78-3.54 (m, 1H), 3.56-3.35 (m, 2H),3.24-3.10 (m, 0.5H), 2.67 (s, 3H), 2.42-2.25 (m, 2H), 1.62-1.39 (m, 3H).93 ¹H NMR (400 MHz, DMSO) δ 13.34 (s, 1H), 9.08-8.71 (m, 1H), 8.54 (d, J= 3.0 Hz, 1H), 8.34-7.93 (m, 2H), 7.13 (s, 1H), 7.00 (dd, J = 6.6, 4.6Hz, 1H), 6.42 (s, 2H), 5.76-5.54 (m, 1H), 3.60-3.46 (m, 1H), 3.46-3.34(m, 2H), 3.21-3.04 (m, 1H), 2.90 (s, 6H), 2.15- 1.81 (m, 4H), 1.52 (d, J= 6.9 Hz, 3H). 94 ¹H NMR (400 MHz, DMSO) δ 13.49 (s, 0.5H), 8.90 (dd, J= 6.7, 1.5 Hz, 1H), 8.55 (dd, J = 4.5, 1.5 Hz, 1H), 8.12 (d, J = 7.1 Hz,2H), 7.15 (s, 1H), 6.99 (dd, J = 6.7, 4.5 Hz, 1H), 5.83-5.60 (m, 1H),4.05-3.86 (m, 2H), 3.85-3.52 (m, 2H), 3.49-3.22 (m, 5H), 1.53 (d, J =6.9 Hz, 3H).

Example 95.N-(1-{7-[(3S)-3-(Acetylamino)pyrrolidin-1-yl]-4-chloro-2H-indazol-6-yl}ethyl)-2-aminopyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. Benzyl[(3S)-1-(6-{1-[({2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-7-yl)pyrrolidin-3-yl]carbamate

The desired compound was prepared according to the procedure of Examples90A-90B, steps 1-8, using benzyl (3S)-pyrrolidin-3-ylcarbamate in step 6instead of 3-pyrrolidinol. LCMS for C₃₉H₅₁ClN₉O₆Si (M+H)⁺: m/z=804.3;Found: 804.5.

Step 2. tert-Butyl[3-({[1-(7-[(3S)-3-aminopyrrolidin-1-yl]-4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-6-yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate

A solution of benzyl[(3S)-1-(6-{1-[({2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilypethoxy]methyl}-2H-indazol-7-yl)pyrrolidin-3-yl]carbamate(0.101 g, 0.126 mmol) in methanol (3.0 mL) was degassed with nitrogen,treated with 30 mg of 10% Pd on carbon (Degussa type), and hydrogenatedwith a balloon of hydrogen for 2 h. The reaction mixture was filteredover a disposable fritted cartridge, rinsed with methanol, andconcentrated to give the desired product (77.8 mg, 92%) as a tan solidthat was used without further purification. LCMS for C₃₁H₄₅ClN₉O₄Si(M+H)⁺: m/z=670.3; Found: 670.5.

Step 3.N-(1-{7-[(3S)-3-(Acetylamino)pyrrolidin-1-yl]-4-chloro-2H-indazol-6-yl}ethyl)-2-aminopyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

A solution of tert-butyl[3-({[1-(7-[(3S)-3-aminopyrrolidin-1-yl]-4-chloro-2-{[2-(trimethylsilypethoxy]methyl}-2H-indazol-6-yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate(38.9 mg, 0.0580 mmol) in dichloromethane (1.1 mL) at 0° C. was treatedwith triethylamine (0.0243 mL, 0.174 mmol) followed by dropwise additonof 0.2 M acetic anhydride in DMF (0.377 mL, 0.0754 mmol). The ice bathwas removed and the reaction mixture was stirred for 30 min. Thereaction mixture was diluted with water (20 mL) and extracted with ethylacetate (30 mL). The organic layer was separated, washed with brine,dried over sodium sulfate, filtered, and concentrated to give theintermediate acetate that still contained the SEM and Boc protectinggroups. This intermediate was dissolved in methanol (0.5 mL), treatedwith 4.0 M hydrogen chloride in dioxane (1.0 mL, 4.0 mmol), and stirredfor 1 hat room temperature and heated at 60° C. for 15 min. Thevolatiles were evaporated to give a crude residue that was purified bypreparative LCMS (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60mL/min) to give two peaks. The second peak that eluted was the desiredproduct (3 mg, 42%). ¹H NMR (400 MHz, DMSO) δ 13.31 (s, 1H), 8.90 (dd,J=6.7, 1.5 Hz, 1H), 8.55 (dd, J=4.5, 1.6 Hz, 1H), 8.29-7.99 (m, 2H),7.15 (s, 1H), 6.99 (dd, J=6.7, 4.5 Hz, 1H), 6.45 (s, 2H), 5.76-5.63 (m,1H), 4.64-4.46 (m, 1H), 3.27-3.19 (m, 1H), 3.10-2.94 (m, 1H), 2.41-2.27(m, 1H), 2.00-1.89 (m, 1H), 1.87 (s, 3H), 1.52 (d, J=7.0 Hz, 3H). LCMSfor C₂₂H₂₅ClN₉O₂ (M+H)⁺: m/z=482.2; Found: 482.1.

Example 96A.2-Amino-N-[1-(4-chloro-7-{(3S)-3-[(methylsulfonyl)amino]pyrrolidin-1-yl}-2H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The desired compound was prepared according to the procedure of Example95, step 3, using 0.2 M methanesulfonyl chloride in DMF instead of 0.2 Macetic anhydride in DMF. ¹H NMR (400 MHz, DMSO) δ 13.28 (s, 1H), 8.89(dd, J=6.7, 1.6 Hz, 1H), 8.56 (dd, J=4.5, 1.6 Hz, 1H), 8.17 (d, J=7.9Hz, 1H), 8.12 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.15 (s, 1H), 6.99 (dd,J=6.7, 4.5 Hz, 1H), 6.44 (s, 2H), 5.79-5.59 (m, 1H), 4.38-4.14 (m, 1H),3.58-3.42 (m, 1H), 3.22-3.11 (m, 1H), 2.95 (s, 3H), 2.45-2.36 (m, 1H),2.14-1.94 (m, 1H), 1.52 (d, J=7.0 Hz, 3H). LCMS for C₂₁H₂₅ClN₉O₃S(M+H)⁺: m/z=518.1; Found: 518.1.

Example 96B.2-Amino-N-[1-(4-chloro-7-{(3R)-3-[(methylsulfonyl)amino]pyrrolidin-1-yl}-2H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. tert-Butyl[(3R)-1-(6-{1-[({2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-7-yl]pyrrolidin-3-ylkarbamate

The desired compound was prepared according to the procedure of Examples90A-90B, steps 1-8, using tert-butyl (3R)-pyrrolidin-3-ylcarbamate instep 6 instead of 3-pyrrolidinol. LCMS for C₃₆H₅₃ClN₉O₆Si (M+H)⁺:m/z=770.4; Found: 770.5.

Step 2.2-Amino-N-(1-{7-[(3R)-3-aminopyrrolidin-1-yl]-4-chloro-2H-indazol-6-yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired compound was prepared according to the procedure of Examples90A, step 9, using tert-butyl[(3R)-1-(6-{1-[({2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilypethoxy]methyl}-2H-indazol-7-yl)pyrrolidin-3-yl]carbamateas the starting material. LCMS for C₂₀H₂₃ClN₉O (M+H)⁺: m/z=440.2; Found:440.2.

Step 3.2-Amino-N-[1-(4-chloro-7-{(3R)-3-[(methylsulfonyl)amino]pyrrolidin-1-yl}-2H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The desired compound was prepared according to the procedure of Example95, step 3, using2-amino-N-(1-{7-[(3R)-3-aminopyrrolidin-1-yl]-4-chloro-2H-indazol-6-yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamideand 0.2 M methanesulfonyl chloride in DMF instead of 0.2 M aceticanhydride in DMF. ¹H NMR (400 MHz, DMSO) δ 13.30 (s, 1H), 8.90 (dd,J=6.7, 1.6 Hz, 1H), 8.55 (dd, J=4.5, 1.6 Hz, 1H), 8.26-7.97 (m, 2H),7.36 (d, J=7.8 Hz, 1H), 7.13 (s, 1H), 6.99 (dd, J=6.7, 4.5 Hz, 1H), 6.43(s, 2H), 5.84-5.54 (m,1H), 4.43-4.09 (m, 1H), 3.76-3.55 (m, 1H),3.20-3.01 (m, 2H), 2.96 (s, 3H), 2.43-2.29 (m, 1H), 2.16-1.87 (m, 1H),1.50 (d, J=6.9 Hz, 3H). LCMS for C₂₁H₂₅ClN₉O₃S (M+H)⁺: m/z=518.1; Found:518.3.

Example 97. Ethyl4-[6-(1-{[(2-aminopyrazolo[1,5-a]pyrimidin-3-yl)carbonyl]amino}ethyl)-4-chloro-2H-indazol-7-yl]cyclohex-3-ene-1-carboxylatebistrifluoroacetate

Step 1. Ethyl4-(6-acetyl-4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-7-yl)cyclohex-3-ene-1-carboxylate

A solution of6-acetyl-4-chloro-2-{[2,-(trimethylsilypethoxy]methyl}-2H-indazol-7-yltrifluoromethanesulfonate (Examples 90A-90B, Step 5, 0.0950 g, 0.201mmol) in toluene (0.712 mL) was added a solution of sodium bicarbonate(0.0321 g, 0.382 mmol) in water (0.475 mL, 26.4 mmol), followed by ethyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate(0.0732 g, 0.261 mmol) and the mixture was bubbled with nitrogen for 5min. Added tetrakis(triphenylphosphine)palladium(0) (0.012 g, 0.010mmol), bubbled with nitrogen for another 5 min, and heated at 80° C. for4.5 h. The reaction mixture was poured into saturated sodium bicarbonatesolution (20 mL) and extracted with ethyl acetate (30 mL). The organicextract was washed with brine, dried over sodium sulfate, filtered, andconcentrated to give a brown gum. Purification by flash columnchromatography using ethyl acetate in hexanes (0%-30%) gave the desiredproduct (78.8 mg, 82%) as a colorless oil. LCMS for C₂₄H₃₄ClN₂O₄Si(M+H)⁺: m/z=477.2; Found: 477.1.

Step 2. Ethyl4-(6-(1-aminoethyl)-4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-7-yl)cyclohex-3-ene-1-carboxylate

The desired compound was prepared according to the procedure of Example1, step 5, using ethyl4-(6-acetyl-4-chloro-2-{[2-(trimethylsilypethoxy]methyl}-2H-indazol-7-yl)cyclohex-3-ene-1-carboxylate as the starting material. LCMS for C₂₄H₃₇ClN₃O₃Si (M+H)⁺:m/z=478.2; Found: 478.2.

Step 3. Ethyl4-(6-{1-[({2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-7-yl)cyclohex-3-ene-1-carboxylate

The desired compound was prepared according to the procedure of Example1, step 6, using ethyl4-(6-(1-aminoethyl)-4-chloro-2-{[2-(trimethylsilypethoxy]methyl}-2H-indazol-7-yl)cyclohex-3-ene-1-carboxylateas the starting material. LCMS for C₃₆H₄₉ClN₇O₆Si (M+H)⁺: m/z=738.3;Found: 738.3.

Step 4. Ethyl4-[6-(1-{[(2-aminopyrazolo[1,5-a]pyrimidin-3-yl)carbonyl]amino}ethyl)-4-chloro-2H-indazol-7-yl]cyclohex-3-ene-1-carboxylatebistrifluoroacetate

The desired compound was prepared according to the procedure of Examples90A-90B, step 9, using ethyl4-(6-{1-[({2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilypethoxy]methyl}-2H-indazol-7-yl)cyclohex-3-ene-1-carboxylateas the starting material. ¹H NMR (400 MHz, DMSO) δ 13.25 (s, 1H), 8.90(d, J=6.7 Hz, 1H), 8.54 (s, 1H), 8.11 (s, 1H), 8.05 (d, J=3.5 Hz, 1H),7.22-7.13 (m, 1H), 7.03-6.94 (m, 1H), 6.38 (s, 2H), 5.99-5.58 (m, 1H),5.44-5.01 (m, 1H), 4.12 (q, J=7.1 Hz, 2H), 2.95 (s, 1H), 2.75-2.56 (m,1H), 2.19-1.96 (m, 2H), 1.91-1.77 (m, 1H), 1.47 (d, J=6.7 Hz, 3H), 1.22(t, J=7.1 Hz, 3H). LCMS for C₂₅H₂₇ClN₇O₃ (M+H)⁺: m/z=508.2; Found:508.2.

Example 98. Benzyl4-[6-(1-{[(2-aminopyrazolo[1,5-a]pyrimidin-3-yl)carbonyl]amino}ethyl)-4-chloro-2H-indazol-7-yl]-3,6-dihydropyridine-1(2H)-carboxylatebis(trifluoroacetate)

The desired compound was prepared according to the procedure of Example97, using benzyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylateas the starting material. LCMS for C₂₉H₂₈ClN₈O₃ (M+H)⁺: m/z=571.2;Found: 571.2.

Example 99.2-Amino-N-{1-[4-chloro-7-(1,2,3,6-tetrahydropyridin-4-yl)-2H-indazol-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidebis(trifluoroacetate)

A solution of benzyl4-[6-(1-{[(2-aminopyrazolo[1,5-a]pyrimidin-3-yl)carbonyl]amino}ethyl)-4-chloro-2H-indazol-7-yl]-3,6-dihydropyridine-1(2H)-carboxylatetrifluoroacetate (Example 98, 20.1 mg, 0.0293 mmol) in methanol (2.5 mL)was treated with 1.0 M hydrogen chloride in water (0.0734 mL, 0.0734mmol), degassed with nitrogen, and treated with 20.1 mg of 10% Pd/C(Degussa type), and hydrogenated with a balloon of hydrogen for 1.5 h.The reaction mixture was filtered over a disposable fritted cartridge,rinsed with methanol, and concentrated to give a crude residue.Purification by preparative LCMS (XBridge C18 Column, eluting with agradient of acetonitrile in water with 0.1% trifluoroacetic acid, atflow rate of 60 mL/min) gave desired product (3 mg, 10%) as a whitesolid. ¹H NMR (400 MHz, DMSO) δ 13.39-13.10 (m, 1H), 8.92 (d, J=6.7 Hz,1H), 8.58 (d, J=3.3 Hz, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 7.20 (s, 1H),7.01 (dd, J=6.6, 4.7 Hz, 1H), 6.51 (s, 1H), 6.39 (s, 2H), 6.12-5.71 (m,1H), 5.49-5.09 (m, 1H), 4.01-3.61 (m, 2H), 3.49 (s, 2H), 1.49 (d, J=6.9Hz, 3H). LCMS for C₂₁H₂₂ClN₈O (M+H)⁺: m/z=437.2; Found: 437.1.

Example 100.2-Amino-N-{1-[4-chloro-7-(4-methoxycyclohex-1-en-1-yl)-2H-indazol-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The desired compound was prepared according to the procedure of Example97, using2-(4-methoxycyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas the starting material. ¹H NMR (400 MHz, DMSO) δ 13.24 (s, 1H), 8.90(d, J=6.3 Hz, 1H), 8.54 (s, 1H), 8.24-7.92 (m, 2H), 7.36-7.05 (m, 1H),7.03-6.95 (m, 1H), 6.41 (s, 2H), 5.83-5.56 (m, 1H), 5.48-5.09 (m, 1H),3.89-3.64 (m, 1H), 3.33 (s, 3H), 2.21-1.97 (m, 2H), 1.96-1.56 (m, 1H),1.47 (d, J=6.8 Hz, 3H). LCMS for C₂₃H₂₅ClN₇O₂ (M+H)⁺: m/z=466.2; Found:466.2.

Example 101.2-Amino-N-{1-[4-chloro-7-(4-cyanocyclohex-1-en-1-yl)-2H-indazol-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The desired compound was prepared according to the procedure of Example97, using4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carbonitrileas the starting material. LCMS for C₂₃H₂₂ClN₈O (M+H)⁺: m/z=466.2; Found:461.1.

Example 102. Methyl1-[6-(1-{[(2-aminopyrazolo[1,5-a]pyrimidin-3-yl)carbonyl]amino}ethyl)-4-chloro-2H-indazol-7-yl]pyrrolidine-3-carboxylatetrifluoroacetate

Step 1. Methyl1-(6-{1-[({2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-7-yl)pyrrolidine-3-carboxylate

The desired compound was prepared according to the procedure of Examples90A-90B, steps 1-8, using methyl pyrrolidine-3-carboxylate hydrochloridein step 6 instead of 3-pyrrolidinol. LCMS for C₃₃H₄₆ClN₈O₆Si (M+H)⁺:m/z=713.3; Found: 713.4.

Step 2. Methyl1-[6-(1-{[(2-aminopyrazolo[1,5-a]pyrimidin-3-yl)carbonyl]amino}ethyl)-4-chloro-2H-indazol-7-yl]pyrrolidine-3-carboxylatetrifluoroacetate

The desired compound was prepared according to the procedure of Examples90A-90B, step 9, using methyl1-(6-{1-[({2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-7-yl)pyrrolidine-3-carboxylateas the starting material. ¹H NMR (400 MHz, DMSO) δ 13.34 (s, 1H), 8.89(d, J=6.9 Hz, 1H), 8.53 (d, J=5.1 Hz, 1H), 8.34-7.93 (m, 2H), 7.11 (d,J=3.1 Hz, 1H), 7.04-6.94 (m, 1H), 6.41 (br s, 1H), 5.71-5.46 (m, 1H),3.49-3.30 (m, 2H), 3.27-3.08 (m, 2H), 2.39-2.22 (m, 2H), 1.61-1.37 (m,3H). LCMS for C₂₂H₂₄ClN₈O₃ (M+H)⁺: m/z=483.2; Found: 483.2.

Examples 103A-103B.2-Amino-N-[1-(4-chloro-7-{3-[(methylamino)carbonyl]pyrrolidin-1-yl}-2H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate (Isomers 1-2)

Step 1.1-(6-{1-[({2-[(tert-Butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-7-yl)pyrrolidine-3-carboxylicacid

A solution of methyl1-(6-{1-[({2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilypethoxy]methyl}-2H-indazol-7-yl)pyrrolidine-3-carboxylate(Example 102, Step 1, 71.8 mg, 0.101 mmol) in tetrahydrofuran (0.50 mL)and methanol (0.50 mL) was treated with 2.0 M lithium hydroxide in water(0.151 mL, 0.302 mmol) and stirred for 16 h. The reaction mixture wascooled at 0° C., diluted with water (5 mL) and 1.0 M hydrogen chloridein water (0.453 mL, 0.453 mmol) dropwise until the pH was acidic, andextracted with ethyl acetate (25 mL). The organic layer was washed withbrine, dried over sodium sulfate, filtered, and concentrated to give thedesired product (65.4 mg, 93%) as a tan solid that was used withoutfurther purification. LCMS for C₃₂H₄₄ClN₈O₆Si (M+H)⁺: m/z=699.3; Found:699.4.

Step 2.2-Amino-N-[1-(4-chloro-7-{3-[(methylamino)carbonyl]pyrrolidin-1-yl}-2H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

A solution of1-(6-{1-[({2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilypethoxy]methyl}-2H-indazol-7-yl)pyrrolidine-3-carboxylicacid (32.5 mg, 0.0465 mmol) in N,N-dimethylformamide (0.50 mL, 6.46mmol) was treated with 2.0 M methylamine in THF (69.7 μL, 0.139 mmol)followed by N,N-diisopropylethylamine (32.4 μL, 0.186 mmol). Thereaction mixture was stirred for a few minutes, treated withbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(28.8 mg, 0.0651 mmol), and stirred at room temperature for 1 h. Thereaction mixture was poured into water (10 mL) and saturated sodiumbicarbonate solution (10 mL) and extracted with ethyl acetate (30 mL).The organic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated to give the intermediate acetate that stillcontained the SEM and Boc protecting groups. This intermediate wasdissolved in methanol (0.50 mL), treated with 4.0 M hydrogen chloride indioxane (1.0 mL, 4.0 mmol), and stirred for 2 h. The volatiles wereevaporated to give a crude residue that was purified by preparative LCMS(XBridge C18 Column, eluting with a gradient of acetonitrile in waterwith 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to give twosets of diastereoisomers with each set containing mixtures ofenantiomers. The first peak that eluted (Example 103A, 6 mg, 22%) andthe second peak that eluted (Example 103B, 7.3 mg, 26%) were both whitesolids. Example 103A: ¹H NMR (400 MHz, DMSO) δ 8.89 (dd, J=6.7, 1.5 Hz,1H), 8.54 (dd, J=4.5, 1.5 Hz, 1H), 8.40-8.26 (m, 1H), 8.20 (d, J=7.9 Hz,1H), 8.11 (s, 1H), 7.12 (s, 1H), 6.98 (dd, J=6.7, 4.5 Hz, 1H), 6.45 (brs, 2H), 5.77-5.50 (m, 1H), 3.39-3.20 (m, 4H), 3.15-2.99 (m, 1H), 2.69(d, J=4.5 Hz, 3H), 2.39-2.24 (m, 1H), 2.18-1.94 (m, 1H), 1.52 (d, J=7.0Hz, 3H). LCMS for C₂₂H₂₅ClN₉O₀₂ (M+H)⁺: m/z=482.2; Found: 482.3. Example103B: ¹H NMR (400 MHz, DMSO) δ 8.90 (d, J=6.5 Hz, 1H), 8.54 (d, J=3.3Hz, 1H), 8.37 (d, J=7.5 Hz, 2H), 8.11 (s, 1H), 7.11 (s, 1H), 7.00 (dd,J=6.5, 4.6 Hz, 1H), 6.44 (br s, 1H), 5.64 (dd, J=7.4 Hz, 1H), 3.41-3.23(m, 6H), 3.23-3.11 (m, 1H), 2.70 (d, J=4.4 Hz, 3H), 2.44-2.27 (m, 1H),2.16-2.01 (m, 1H), 1.50 (d, J=7.0 Hz, 3H). LCMS for C22H25C1N902 (M+H)⁺:m/z=482.2; Found: 482.3.

Example 104.N-(1-(7-((S)-3-Acetamidopiperidin-1-yl)-4-chloro-1H-indazol-6-yl)ethyl)-2-aminopyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1. tert-Butyl[3-({[1-(7-[(3S)-3-aminopiperidin-1-yl]-4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-6-yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate

The desired compound was prepared according to the procedure of Example95, steps 1-2 using benzyl (3S)-piperidin-3-ylcarbamate. LCMS forC₃₂H₄₇ClN₉O₄Si (M+H)⁺: m/z=684.3; Found: 684.5.

Step 2.N-(1-(7-((S)-3-Acetamidopperidin-1-yl)-4-chloro-1H-indazol-6-yl)ethyl)-2-aminopyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The desired compound was prepared according to the procedure of Example95, step 3 using tert-butyl[3-({[1-(7-[(3S)-3-aminopiperidin-1-yl]-4-chloro-2-{[2-(trimethyl)ethoxy]methyl}-2H-indazol-6-yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamateas the starting material. LCMS for C₂₃H₂₇ClN₉O₂ (M+H)⁺: m/z=496.2;Found: 496.3.

Example 105.2-Amino-N-[1-(4-chloro-7-{(3S)-3-[(methylsulfonyl)amino]piperidin-1-yl}-2H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The desired compound was prepared according to the procedure of Example95, step 3, using tert-butyl[3-({[1-(7-[(3S)-3-aminopiperidin-1-yl]-4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-6-yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamateand 0.2 M methanesulfonyl chloride in DMF instead of 0.2 M aceticanhydride in DMF. LCMS for C22H27C1N903S (M+H)⁺: m/z=532.2; Found:532.3.

Example 106. Ethyl1-[6-(1-{[(2-aminopyrazolo[1,5-a]pyrimidin-3-yl)carbonyl]amino}ethyl)-4-chloro-2H-indazol-7-yl]piperidine-4-carboxylatetrifluoroacetate

Step 1. Ethyl1-(6-{1-[({2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-7-yl)piperidine-4-carboxylate

The desired compound was prepared according to the procedure of Examples90A-90B, steps 1-8, using ethyl piperidine-4-carboxylate in step 6instead of 3-pyrrolidinol. LCMS for C₃₅H₅₀ClN₈O₆Si (M+H)⁺: m/z=741.3;Found: 741.5.

Step 2. Ethyl1-[6-(1-{[(2-aminopyrazolo[1,5-a]pyrimidin-3-yl)carbonyl]amino}ethyl)-4-chloro-2H-indazol-7-yl]piperidine-4-carboxylatetrifluoroacetate

The desired compound was prepared according to the procedure of Examples90A-90B, step 9, using ethyl1-(6-{1-[({2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilypethoxy]methyl}-2H-indazol-7-yl)piperidine-4-carboxylateas the starting material. ¹H NMR (400 MHz, DMSO) δ 13.38 (s, 1H), 8.90(d, J=6.7 Hz, 1H), 8.52 (d, J=3.2 Hz, 1H), 8.23-8.00 (m, 2H), 7.11 (s,1H), 6.99 (dd, J=6.7, 4.6 Hz, 1H), 6.42 (s, 2H), 5.79-5.58 (m, 1H), 4.12(q, J=7.0 Hz, 2H), 3.59-3.43 (m, 1H), 3.15-2.99 (m, 1H), 2.88-2.74 (m,1H), 2.70-2.54 (m, 1H), 2.03-1.89 (m, 2H), 1.89-1.71 (m, 2H), 1.50 (d,J=6.9 Hz, 3H), 1.22 (t, J=7.1 Hz, 3H). LCMS for C₂₄H₂₈ClN₈O₃ (M+H)⁺:m/z=511.2; Found: 511.3.

Example 107.2-Amino-N-[1-(4-chloro-7-{4-[(methylamino)carbonyl]piperidin-1-yl}-2H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

Step 1.1-(6-{1-[({2-[(tert-Butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-7-yl)piperidine-4-carboxylicacid

The desired compound was prepared according to the procedure of Examples103A-103B, step 1, using ethyl1-(6-{1-[({2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazol-7-yl)piperidine-4-carboxylateas the starting material. LCMS for C₃₃H₄₆ClN₈O₆Si (M+H)⁺: m/z=713.3;Found: 713.4.

Step 2.2-Amino-N-[1-(4-chloro-7-{4-[(methylamino)carbonyl]piperidin-1-yl}-2H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The desired compound was prepared according to the procedure of Examples103A-103B, step 2, using1-(6-{1-[({2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilypethoxy]methyl}-2H-indazol-7-yl)piperidine-4-carboxylicacid as the starting material. ¹H NMR (400 MHz, DMSO) δ 13.41 (br s,0.5H), 8.90 (dd, J=6.7, 1.5 Hz, 1H), 8.55 (dd, J=4.5, 1.5 Hz, 1H),8.23-8.01 (m, 2H), 7.77 (d, J=4.6 Hz, 1H), 7.09 (s, 1H), 6.99 (dd,J=6.7, 4.5 Hz, 1H), 5.81-5.63 (m, 1H), 3.61-3.44 (m, 1H), 3.38-3.22 (m,1H), 3.16-2.98 (m, 1H), 2.90-2.73 (m, 1H), 2.60 (d, J=4.5 Hz, 3H),2.44-2.28 (m, 2H), 1.98-1.67 (m, 4H), 1.50 (d, J=6.9 Hz, 3H). LCMS forC₂₃H₂₇ClN₉O₂ (M+H)⁺: m/z=496.2; Found: 496.3.

Example 108.2-Amino-N-[1-(4-chloro-7-{4-[(dimethylamino)carbonyl]piperidin-1-yl}-2H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The desired compound was prepared according to the procedure of Examples103A-103B using1-(6-{1-[({2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl}carbonyl)amino]ethyl}-4-chloro-2-{[2-(trimethylsilypethoxy]methyl}-2H-indazol-7-yl)piperidine-4-carboxylicacid and 2.0 M dimethylamine in THF instead of 2.0 M methylamine in THF.¹H NMR (400 MHz, DMSO) δ 13.38 (s, 0.5H), 8.89 (dd, J=6.7, 1.5 Hz, 1H),8.55 (dd, J=4.5, 1.5 Hz, 1H), 8.23-8.02 (m, 2H), 7.10 (s, 1H), 6.99 (dd,J=6.7, 4.5 Hz, 1H), 5.81-5.57 (m, 1H), 3.65-3.47 (m, 1H), 3.46-3.31 (m,1H), 3.16-3.00 (m, 4H), 3.01-2.91 (m, 1H), 2.86 (s, 3H), 2.83-2.74 (m,1H), 2.01-1.63 (m, 4H), 1.51 (d, J=6.9 Hz, 3H). LCMS for C₂₄H₂₉ClN₉O₂(M+H)⁺: m/z=510.2; Found: 510.3.

Examples 109-111

The following Examples 109-111 of Table 7 were synthesized according tothe procedure of Example 56. NMR data for the compounds of Table 7 areprovided in Table 7a.

TABLE 7

Ex. No. Name R LCMS 109 2-Amino-N-{1-[4-chloro-7-(1,1-dioxido-1,4-thiazepan-4-yl)pyrazolo[1,5-a]pyridin-6-yl]-ethyl}pyrazolo[1,5-a]pyrimidine-3-carbox- amide trifluoroacetate

for C₂₁H₂₄ClN₈O₃S (M + H)⁺: m/z = 503.1; Found: 503.2 1102-Amino-N-{1-[4-chloro-7-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)pyrazolo[1,5-a]-pyridin-6-yl]ethyl}pyrazolo[1,5-a]- pyrimidine-3-carboxamidetrifluoroacetate

for C₂₀H₂₃ClN₉O₃S (M + H)⁺: m/z = 504.1; Found: 504.3 1112-Amino-N-{1-[4-chloro-7-(2,2-dimethyl-1,1-dioxidothiomorpholin-4-yl)pyrazolo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]- pyrimidine-3-carboxamidetrifluoroacetate

for C₂₂H₂₆ClN₈O₃S (M + H)⁺: m/z = 517.2; Found: 517.1

TABLE 7a Ex. No. ¹H NMR Data 109 ¹H NMR (400 MHz, DMSO) δ 8.91 (d, J =6.4 Hz, 1H), 8.65-8.50 (m, 1H), 8.24-7.96 (m, 2H), 7.48 (s, 1H),7.08-6.90 (m, 1H), 6.72 (d, J = 2.2 Hz, 1H), 6.39 (br s, 2H), 5.95-5.56(m, 1H), 4.00-3.67 (m, 3H), 3.66-3.40 (m, 3H), 3.16-3.02 (m, 1H), 2.38-2.25 (m, 0.5H), 2.20-2.08 (m, 1H), 1.54 (d, J = 6.8 Hz, 3H). 110 ¹H NMR(400 MHz, DMSO) δ 8.91 (dd, J = 6.7, 1.5 Hz, 1H), 8.71-8.43 (m, 1H),8.18- 8.04 (m, 2H), 7.76-7.64 (m, 0.5H), 7.64-7.55 (m, 0.5H), 7.44 (s,1H), 7.01 (dd, J = 6.6, 4.7 Hz, 1H), 6.71 (d, J = 2.2 Hz, 1H), 5.90-5.68(m, 1H), 3.48-3.26 (m, 3H), 3.25-3.04 (m, 2H), 1.52 (t, J = 6.8 Hz, 3H).111 ¹H NMR (400 MHz, DMSO) δ 9.12-8.75 (m, 1H), 8.65-8.45 (m, 1H),8.25-8.01 (m, 2H), 7.53 (s, 0.66H), 7.43 (s, 0.33H), 7.08-6.94 (m, 1H),6.71 (d, J = 2.2 Hz, 1H), 6.41 (s, 2H), 5.97-5.79 (m, 0.66H), 5.78-5.58(m, 0.33H), 4.41-4.26 (m, 0.33H), 4.27- 4.15 (m, 1H), 4.14-3.96 (m,0.66H), 3.81-3.55 (m, 2H), 3.28-3.15 (m, 1H), 3.08 (d, J = 12.7 Hz, 1H),1.68 (s, 1H), 1.64 (s, 2H), 1.59-1.47 (m, 3H), 1.21 (d, J = 6.8 Hz, 3H).

Examples 112A-112B.2-Amino-N-{1-[3,4-dichloro-7-(2-methyl-1,1-dioxidothiomorpholin-4-yl)pyrazolo[1,5-a]pyridin-6-yl]ethy1}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate (Isomers 1-2)

Step 1. 1-(3,4,7-Trichloropyrazolo[1,5-a]pyridin-6-yl)ethanone

A solution of 1-(4,7-dichloropyrazolo[1,5-a]pyridin-6-yl)(ethanone(Example 56, Step 7, 38.0 mg, 0.166 mmol) in N,N-dimethylformamide (1.14mL) was treated with N-chlorosuccinimide (33.2 mg, 0.249 mmol) andstirred at 50° C. for 2 h. The reaction mixture was diluted with water(15 mL) and saturated sodium bicarbonate solution (15 mL) and extractedwith ethyl acetate (30 mL). The organic layer was separated, washed withbrine, dried over sodium sulfate, filtered, and concentrated to give thedesired product (46.6 mg, >100%) as a yellow solid that was used withoutfurther purification. LCMS for C₉H₆Cl₃N₂O (M+H)⁺: m/z=263.0, 264.9;Found: 263.0, 264.9.

Step 2.1-[3,4-Dichloro-7-(2-methyl-1,1-dioxidothiomorphohn-4-yl)pyrazolo[1,5-a]pyridin-6-yl]ethanone

A mixture of 1-(3,4,7-trichloropyrazolo[1,5-a]pyridin-6-yl)ethanone(16.0 mg, 0.0607 mmol), 2-methylthiomorpholine 1,1-dioxide hydrochloride(28.2 mg, 0.152 mmol), and N,N-diisopropylethylamine (52.9 μL, 0.304mmol) was heated at 140° C. in the microwave for 1 h. The reactionmixture was diluted with ethyl acetate (30 mL), washed with water (20mL) and brine (10 mL), dried over sodium sulfate, filtered, andconcentrated to give the desired product (25.6 mg, >100%) as a brownsolid that was used without further purification. LCMS forC₁₄H₁₆Cl₂N₃O₃S (M+H)⁺: m/z=376.0, 378.0; Found: 376.0, 378.0.

Step 3.2-Amino-N-{1-[3,4-dichloro-7-(2-methyl-1,1-dioxidothiomorphohn-4-yl)pyrazolo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

The desired compound was prepared according to the procedure of Example56, step 9, using1-[3,4-dichloro-7-(2-methyl-1,1-dioxidothiomorpholin-4-yl)pyrazolo[1,5-a]pyridin-6-yl]ethanoneas the starting material. The crude reaction mixture was evaporated andthe crude residue was purified by preparative LCMS (XBridge C18 Column,eluting with a gradient of acetonitrile in water with 0.1%trifluoroacetic acid, at flow rate of 60 mL/min) to give two sets ofdiastereoisomers with each set containing mixtures of enantiomers. Thefirst peak that eluted (Example 112A, 4.3 mg, 11%) and the second peakthat eluted (Example 112B, 3.9 mg, 10%) were both white solids. Example112A: ¹H NMR (400 MHz, DMSO) δ 9.06-8.75 (m, 1H), 8.54 (d, J=3.0 Hz,1H), 8.25 (d, J=5.5 Hz, 1H), 8.17-7.99 (m, 1H), 7.55 (s, 1H), 7.00 (dd,J=6.7, 4.6 Hz, 1H), 6.50 (s, 0.66H), 6.42 (s, 1.33H), 5.80-5.58 (m, 1H),4.34-4.13 (m, 1H), 4.06-3.89 (m, 0.5H), 3.82-3.72 (m, 1H), 3.72-3.59 (m,1H), 3.59-3.38 (m, 2H), 1.54 (d, J=7.0 Hz, 3H), 1.48 (d, J=6.9 Hz, 1H),1.11 (d, J=6.7 Hz, 2H). LCMS for C₂₁H₂₃Cl₂N₈O₃S (M+H)⁺: m/z=537.1;Found: 537.1. Example 112B: ¹H NMR (400 MHz, DMSO) δ 8.90 (dd, J=6.7,1.5 Hz, 1H), 8.62-8.49 (m, 1H), 8.31-8.21 (m, 1H), 8.08 (d, J=6.7 Hz,1H), 7.53 (s, 0.75H), 7.47 (s, 0.25H), 7.00 (dd, J=6.7, 4.5 Hz, 1H),6.50 (s, 0.5H), 6.41 (s, 1.5H), 5.77-5.60 (m, 0.75H), 5.58-5.42 (m,0.25H), 4.26-4.15 (m, 0.25H), 4.15-3.98 (m, 1H), 3.96-3.82 (m, 1H),3.63-3.48 (m, 2.5H), 3.47-3.38 (m, 0.5H), 3.22 (d, J=12.7 Hz, 1H), 1.54(d, J=7.0 Hz, 3H), 1.47 (d, J=6.2 Hz, 0.5H), 1.11 (d, J=6.8 Hz, 2.5H).LCMS for C₂₁H₂₃Cl₂N₈O₃S (M+H)⁺: m/z=537.1; Found: 537.1.

Examples 113-116

The following Examples 113-116 of Table 8 were synthesized according tothe procedure of Examples 112A-112B. NMR data for the compounds of Table8 are provided in Table 8a.

TABLE 8

Ex. No. Name R LCMS 113 2-Amino-N-{1-[3,4-dichloro-7-(1,1-dioxido-thiomorpholin-4-yl)pyrazolo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carbox- amide trifluoroacetate

for C₂₀H₂₁Cl₂N₈O₃S (M + H)⁺: m/z = 523.1; Found: 523.2 1142-Amino-N-{1-[3,4-dichloro-7-(1,1-dioxido-1,4-thiazepan-4-yl)pyrazolo[1,5-a]pyridin-6-yl[ethyl}pyrazolo[1,5-a]pyrimidine-3-carbox- amide trifluoroacetate

for C₂₁H₂₃Cl₂N₈O₃S (M + H)⁺: m/z = 537.1; Found: 537.1 1152-Amino-N-{1-[3,4-dichloro-7-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)pyrazolo[1,5-a]-pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine- 3-carboxamidetrifluoroacetate

for C₂₀H₂₂Cl₂N₉O₃S (M + H)⁺: m/z = 538.1; Found: 538.1 1162-Amino-N-{1-13,4-dichloro-7-(2,2-dimeth-yl-1,1-dioxidothiomorpholin-4-yl)pyrazolo-[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]- pyrimidine-3-carboxamidetrifluoroacetate

for C₂₂H₂₅Cl₂N₈O₃S (M + H)⁺: m/z = 551.1; Found: 551.1

TABLE 8a Ex. No. ¹H NMR Data 113 ¹H NMR (400 MHz, DMSO) δ 8.90 (d, J =6.7 Hz, 1H), 8.55 (d, J = 4.4 Hz, 1H), 8.25 (s, 1H), 8.08 (d, J = 6.8Hz, 1H), 7.52 (s, 1H), 7.00 (dd, J = 6.6, 4.6 Hz, 1H), 6.40 (br s, 2H),5.88-5.47 (m, 1H), 4.26-3.97 (m, 2H), 1.53 (d, J = 6.9 Hz, 3H). 114 ¹HNMR (400 MHz, DMSO) δ 8.91 (d, J = 6.6 Hz, 1H), 8.65-8.50 (m, 1H), 8.24(s, 1H), 8.16-8.02 (m, 1H), 7.51 (s, 1H), 7.08-6.93 (m, 1H), 6.40 (br s,2H), 5.86-5.55 (m, 1H), 3.95-3.83 (m, 0.5H), 3.83-3.62 (m, 2H),3.62-3.40 (m, 3H), 3.19-3.02 (m, 0.5H), 2.41-2.22 (m, 0.5H), 2.19-1.99(m, 3H), 1.53 (d, J = 6.8 Hz, 3H). 115 ¹H NMR (400 MHz, DMSO) δ 8.91 (d,J = 6.8 Hz, 1H), 8.65-8.51 (m, 1H), 8.23 (s, 1H), 8.17-8.03 (m, 1H),7.74-7.63 (m, 0.66H), 7.63-7.54 (m, 0.33H), 7.49 (s, 1H), 7.10-6.93 (m,1H), 6.50 (s, 0.5H), 6.39 (s, 2H), 5.87-5.63 (m, 1H), 4.08-3.91 (m, 1H),3.89-3.66 (m, 2H), 3.62-3.47 (m, 1H), 3.21-3.07 (m, 2H), 1.58-1.42 (m,3H). 116 ¹H NMR (400 MHz, DMSO) δ 9.08-8.76 (m, 1H), 8.64-8.47 (m, 1H),8.27 (s, 1H), 8.10 (d, J = 6.5 Hz, 1H), 7.57 (s, 0.75H), 7.46 (s,0.25H), 7.07-6.94 (m, 1H), 6.52 (s, 0.5H), 6.41 (s, 2H), 5.92-5.73 (m,0.75H), 5.71-5.53 (m, 0.25H), 4.31-4.19 (m, 0.33H), 4.19-4.08 (m, 1H),4.08-3.94 (m, 0.66H), 3.82-3.58 (m, 2H), 3.10 (d, J = 12.4 Hz, 0.75H),1.66 (s, 1H), 1.62 (s, 2H), 1.58-1.47 (m, 3H), 1.21 (d, J = 8.2 Hz, 3H).

Example 117.2-Amino-N-[1-(8-cyclopropyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1. 1-(8-Cyclopropyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanone

A degassed mixture of1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanone (30. mg, 0.11mmol, from Example 27, Step 7), cyclopropylboronic acid (14 mg, 0.17mmol, Aldrich), Cs₂CO₃ (180 mg, 0.55 mmol) andtetrakis(triphenylphosphine)palladium(0) (6.4 mg, 0.0055 mmol) in1,4-dioxane (1.2 mL) and water (0.30 mL) was heated to 80° C. for 1hour. Additional tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.011mmol) and cyclopropylboronic acid (28 mg, 0.33 mmol) were added. Themixture was degassed, sealed and heated to 80° C. overnight. Additionalcyclopropylboronic acid (19 mg, 0.22 mmol), Cs₂CO₃ (72 mg, 0.22 mmol)and tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.011 mmol) wereadded. The mixture was again degassed and heated to 100° C. for 3 hours.Upon cooling to room temperature, the reaction mixture was partitionedbetween EtOAc and water. The organic layer was dried over Na₂SO₄,filtered and concentrated. The product was purified by preparativeHPLC/MS (pH=10). Yield: 15 mg, 57%. LCMS calculated for C₁₈H₁₇N₂Omonoisotopic (M+H)⁺: m/z=277.1; found 277.1.

Step 2.2-Amino-N-[1-(8-cyclopropyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Using 1-(8-cyclopropyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanone (15mg, 0.054 mmol), Steps 11 and 12 of Example 26 were followed to affordthe title compound. Yield: 5.2 mg. LCMS calculated for C₂₅H₂₄N₇Omonoisotopic (M+H)⁺: m/z=438.2; found 438.2. ¹ H NMR (400 MHz, d₆-DMSO)δ 8.93 (dd, J=6.7, 1.4 Hz, 1H), 8.55 (dd, J=4.4, 1.4 Hz, 1H), 8.40 (s,1H), 8.15 (s, 1H), 8.07 (d, J=6.9 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H),7.74-7.53 (m, 4H), 7.02 (dd, J=6.7, 4.5 Hz, 1H), 6.93 (s, 1H), 6.40 (brs, 2H), 4.81 (p, J=6.9 Hz, 1H), 2.24 (tt, J=8.4, 5.2 Hz, 1H), 1.42 (d,J=6.9 Hz, 3H), 1.16-1.01 (m, 2H), 1.01-0.91 (m, 1H), 0.91-0.79 (m, 1H).

Example 118.2-Amino-N-{1-[8-chloro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1. Methyl 5-chloro-6-cyano-2-(1H-pyrazol-4-yl)nicotinate

To a solution of methyl 2,5-dichloro-6-cyanonicotinate (0.80 g, 3.5mmol, Example 26, Step 3), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(2.0 g, 6.9 mmol, Aldrich), and cesium fluoride (1.6 g, 10. mmol) inwater (6.08 mL) and 1,4-dioxane (15.8 mL) was addedbis(triphenylphosphine)palladium(II) chloride (0.14 g, 0.21 mmol). Themixture was degassed by sparging the solution with nitrogen for 10minutes. The reaction was heated to 80° C. for 2 hours and 20 minutes.Upon cooling to room temperature, saturated NaHCO₃ was added, and themixture was extracted with EtOAc. The organic extract was dried overNa₂SO₄, filtered, and concentrated. The product was purified by flashchromatography (0-50% EtOAc in hexanes). Yield: 0.76 g, 90%. LCMScalculated for C₁₁H₈ClN₄O₂monoisotopic (M+H)⁺: m/z=263.0; found 263.0.

Step 2. Methyl8-chloro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridine-6-carboxylate

A degassed solution of methyl5-chloro-6-cyano-2-(1H-pyrazol-4-yl)nicotinate (0.79 g, 2.7 mmol) inMeOH (44. mL) was treated with Raney® Nickel 2800 (0.030 mL of a slurryin water). The mixture was stirred under 1 atm of H₂ (provided by aballoon) for 2 hours. An additional portion of Raney®Nickel 2800 (0.030mL) was added, and the mixture stirred under an atmosphere of H₂ for 2additional hours. The reaction mixture was filtered through Celite® andthe filter aid was washed with MeOH. The filtrate was concentrated. Thecrude product was dissolved in DMF (6.0 mL), andN,N-diisopropylethylamine (1.2 mL, 6.8 mmol) and acetic anhydride (0.28mL, 3.0 mmol) were added. After 30 minutes, the reaction was quenched bythe addition of saturated NaHCO₃ solution, and the aqueous mixture wasextracted with EtOAc. The combined organic extracts were washed withwater and brine, dried over Na₂SO₄, filtered, and concentrated to affordthe crude product as a solid. The crude solid was suspended inphosphoryl chloride (5.0 mL, 54 mmol) and stirred at room temperaturefor 4 hours. The reaction mixture was poured slowly onto crushed ice,then treated with solid K₂CO₃ to achieve pH=10. The aqueous mixture wasextracted with three portions of DCM.

The combined organic extracts were dried over Na₂SO₄, filtered andconcentrated. The product was purified by flash chromatography (0-5%MeOH in DCM). Yield: 0.40 g, 51%. LCMS calculated forC₁₃H₁₂ClN₄O₂monoisotopic (M+H)⁺: m/z=291.0; found 291.0.

Step 3.2-Amino-N-{1-[8-chloro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Using methyl8-chloro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridine-6-carboxylate,Steps 8-12 of Example 26 were followed to afford the title compound.LCMS calculated for C₂₀H₁₉ClN₉O monoisotopic (M+H)⁺: m/z=436.1; found436.2. ¹H NMR (400 MHz, d₆-DMSO) δ 8.92 (dd, J=6.7, 1.6 Hz, 1H), 8.56(dd, J=4.5, 1.5 Hz, 1H), 8.07-7.95 (m, 3H), 7.90 (s, 1H), 7.33 (s, 1H),7.02 (dd, J=6.7, 4.5 Hz, 1H), 4.73 (p, J=6.4 Hz, 1H), 2.03 (s, 3H), 1.41(d, J=7.0 Hz, 3H).

Examples 119-121

Examples 119-121 in Table 9 were prepared by the method of Example 118.NMR data for the compounds of Table 9 are provided in Table 9a.

TABLE 9

Ex. No. Name R = LCMS 119 2-Amino-N-{1-[8-chloro-3-methyl-5-(1-methyl-1H-pyrazol-4-yl)imidazo[1,5-a]-pyridin-6-yl]ethyl}pyrazolo[1,5-a]- pyrimidine-3-carboxamide trifluoro-acetate salt (racemic mixture prepared)

Calculated for C₂₁H₂₁ClN₉O monoisotopic (M + H)⁺: m/z = 450.1; found:450.1 120 2-Amino-N-[1-(8-chloro-3-methyl-5-pyridin-3-ylimidazo[1,5-a]pyridin-6-yl)-ethyl]pyrazolo[1,5-a]pyrimidine-3- carboxamide trifluoroacetate salt(racemic mixture prepared)

Calculated for C₂₂H₂₀ClN₈O monoisotopic (M + H)⁺: m/z = 447.1; found:447.1 121 2-Amino-N-[1-(8-chloro-3-methyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]-pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate salt (racemicmixture prepared)

Calculated for C₂₃H₂₁ClN₇O monoisotopic (M + H)⁺: m/z = 446.2; found:446.1

TABLE 9a Ex. No. ¹H NMR 119 ¹H NMR (400 MHz, d₆-DMSO) δ 8.92 (dd, J =6.7, 1.5 Hz, 1H), 8.57 (dd, J = 4.5, 1.0 Hz, 1H), 8.11 (s, 0.5H), 8.09(s, 0.5H), 8.03 (d, J = 6.4 Hz, 1H), 7.91 (s, 1H), 7.81 (s, 0.5H), 7.75(s, 0.5H), 7.33 (s, 1H), 7.02 (dd, J = 6.7, 4.6 Hz, 1H), 4.76 (p, J =6.4 Hz, 1H), 4.01 (s, 1.5H), 3.98 (s, 1.5H), 2.08 (s, 3H), 1.41 (d, J =7.0 Hz, 3H). 120 ¹H NMR (400 MHz, d₆-DMSO) δ 9.05 (d, J = 1.5 Hz, 0.5H),8.95-8.90 (m, 1H), 8.85 (dd, J = 4.9, 1.3 Hz, 1H), 8.83 (d, J = 1.6 Hz,0.5H), 8.56 (dd, J = 4.5, 1.6 Hz, 1H), 8.32 (dt, J = 8.1, 1.9 Hz, 0.5H),8.12 (dt, J = 7.8, 1.8 Hz, 0.5H), 8.05 (d, J = 6.3 Hz 0.5H), 8.05 (d, J= 6.2 Hz 0.5H), 7.95 (s, 1H), 7.72 (dd, J = 7.8, 5.0 Hz, 0.5H), 7.67(dd, J = 7.7, 4.9 Hz, 0.5H), 7.42 (s, 0.5H), 7.42 (s, 0.5H), 7.02 (dd, J= 6.7, 4.5 Hz, 1H), 4.49 (p, J = 7.3, 6.7 Hz, 1H), 1.85 (s, 3H), 1.43(d, J = 7.5 Hz, 1.5H), 1.41 (d, J = 7.3 Hz, 1.5H) 121 ¹H NMR (400 MHz,d₆-DMSO) δ 8.91 (dd, J = 6.7, 1.5 Hz, 1H), 8.55 (dd, J = 4.5, 1.5 Hz,1H), 8.03 (d, J = 6.3 Hz, 1H), 7.97 (s, 1H), 7.86-7.78 (m, 1H),7.70-7.53 (m, 4H), 7.38 (s, 1H), 7.01 (dd, J = 6.7, 4.5 Hz, 1H), 4.59(p, J = 6.7 Hz, 1H), 1.83 (s, 3H), 1.38 (d, J = 7.0 Hz, 3H)

Example 122.2-Amino-N-{1-[1,8-dichloro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.1-[1,8-Dichloro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethanone

1-[8-Chloro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethanone was prepared by treating theproduct of Example 118, Step 2 with the methods of Example 26, Steps 8through 10 to provide1-[8-chloro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethanone.To a solution of1-[-8-chloro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethanone(15.0 mg, 0.0546 mmol) in DMF (0.20 mL) was added N-chlorosuccinimide(8.7 mg, 0.066 mmol) in DMF (0.20 mL). The mixture was stirred atambient temperature for 22 hours. Saturated NaHCO₃ was added, and themixture was extracted with EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated. The product waspurified by flash chromatography (0-100% EtOAc in hexanes). Yield: 5.6mg, 33%. LCMS calculated for C₁₃H₁₁Cl₂N₄O monoisotopic (M+H)⁺:m/z=309.0; found 309.1.

Step 2.2-Amino-N-{1-[1,8-dichloro-3-methyl-5-(1I-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Using1-[1,8-dichloro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethanone(5.0 mg, 0.016 mmol), Steps 11 and 12 of Example 26 were followed toafford the title compound. Yield: 2.4 mg. LCMS calculated forC₂₀H₁₈Cl₂N₉O monoisotopic (M+H)⁺: m/z=470.1; found 470.2. ¹H NMR (400MHz, d₆MSO) δ 8.91 (dd, J=6.7, 1.6 Hz, 1H), 8.56 (dd, J=4.5, 1.6 Hz,1H), 8.05-7.92 (m, 3H), 7.03 (s, 1H), 7.01 (dd, J=6.8, 4.5 Hz, 1H), 4.67(p, J=7.3, 6.8 Hz, 1H), 1.88 (s, 3H), 1.37 (d, J=7.0 Hz, 3H).

Example 123.2-Amino-N-{1-[8-chloro-1-fluoro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.1-[8-Chloro-1-fluoro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethanone

To a solution of1-[8-chloro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethanone(45 mg, 0.16 mmol, prepared by treating the product of Example 118, Step2 with the methods of Example 26, Steps 8 through 10) in DMF (1.8 mL)was added 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (254 mg,1.15 mmol, Aldrich). The reaction was heated to 60° C. for 3 hours. Uponcooling, 1N NaOH was added, and the mixture was extracted with threeportions of DCM. The combined organic extracts were washed with brine,dried over Na₂SO₄, filtered and concentrated. The product was purifiedby preparative HPLC/MS (pH=2). Acetonitrile was evaporated from theeluent and the aqueous mixture was basified to pH=8 by the addition ofsolid NaHCO₃. The basic aqueous mixture was extracted with two portionsof DCM and the extracts were dried over Na₂SO₄, filtered andconcentrated. Yield: 10. mg, 14%. LCMS calculated for C₁₃H₁₁ClFN₄Omonoisotopic (M+H)⁺: m/z=293.1; found 293.0.

Step 2.2-Amino-N-{1-[8-chloro-1-fluoro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(racemic mixture prepared)

Using1-[8-chloro-1-fluoro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethanone(10.0 mg, 0.024 mmol), Steps 11 and 12 of Example 26 were followed toafford the title compound. The product was purified by preparativeHPLC/MS (pH=10). Yield: 2.5 mg. LCMS calculated for C₂₀H₁₈ClFN₉Omonoisotopic (M+H)⁺: m/z=454.1; found 454.1. ¹H NMR (400 MHz, d₆-DMSO) δ8.91 (dd, J=6.7, 1.6 Hz, 1H), 8.56 (dd, J=4.5, 1.5 Hz, 1H), 7.99 (d,J=6.6 Hz, 1H), 7.99 (br s, 2H), 7.01 (dd, J=6.7, 4.5 Hz, 1H), 6.89 (s,1H), 6.44 (s, 2H), 4.67 (p, J=7.1 Hz, 1H), 1.84 (s, 3H), 1.37 (d, J=7.0Hz, 3H).

Example 124.2-Amino-N-{1-[8-chloro-3-methyl-5-phenyl-1-(trifluoromethypimidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.1-(8-Chloro-1-iodo-3-methyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanone

1-(8-Chloro-3-methyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanone wasprepared by the method of Example 26, Steps 1-10 substitutingphenylboronic acid (Aldrich) for (3-fluorophenyl)boronic acid in Step 4.To a solution of1-(8-chloro-3-methyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanone (0.28g, 0.98 mmol) in DMF (5.3 mL) was added N-iodosuccinimide (0.24 g, 1.1mmol). After stirring for 70 minutes, the reaction was quenched by theaddition of saturated NaHCO₃ solution. The mixture was extracted withEtOAc, and the combined organic extracts were dried over Na₂SO₄,filtered and concentrated. The product was purified by flashchromatography (0-20% EtOAc in hexanes). Yield: 0.40 g, 99%. LCMScalculated for C₁₆H₁₃ClIN₂O monoisotopic (M+H)⁺: m/z=411.0; found 411.0.

Step 2.1-[8-Chloro-3-methyl-5-phenyl-1-(trilluoromethyl)imidazo[1,5-a]pyridin-6-yl]ethanone

To a solution of1-(8-chloro-1-iodo-3-methyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanone(40. mg, 0.097 mmol) in DMF (2.0 mL) was added copper(I) iodide (93 mg,0.49 mmol), hexamethylphosphoramide (169 μL, 0.974 mmol), and methyldifluoro(fluorosulfonyl)acetate (80. μL, 0.63 mmol, Aldrich). Themixture was heated to 80° C. under nitrogen for 2 hours. Upon cooling toroom temperature, water was added. The mixture was extracted with Et₂O.The combined organic extracts were washed with water and diluted withEtOAc. The organic layer was washed with saturated NaHCO₃ solution, thenwith brine, dried over Na₂SO₄, filtered and concentrated. The productwas purified by flash chromatography (0-20% EtOAc in hexanes). Yield:0.030 g, 87%. LCMS calculated for C₁₇H₁₃ClF₃N₂O monoisotopic (M+H)⁺:m/z=353.1; found 353.0.

Step 3.2-Amino-N-{1-[8-chloro-3-methyl-5-phenyl-1-(trilluoromethyl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Using 1[8-chloro-3-methyl-5-phenyl-1-(trifluoromethyl)imidazo[1,5-a]pyridin-6-yl]ethanone(7.3 mg, 0.021 mmol), Steps 11 and 12 of Example 26 were followed toafford the title compound. Yield: 6.1 mg. LCMS calculated forC₂₄H₂₀ClF₃N₇O monoisotopic (M+H)⁺: m/z=514.1; found 514.1. ¹H NMR (400MHz, d₆-DMSO) δ 8.92 (dd, J=6.7, 1.5 Hz, 1H), 8.56 (dd, J=4.5, 1.5 Hz,1H), 8.05 (d, J=6.3 Hz, 1H), 7.84-7.79 (m, 1H), 7.71-7.54 (m, 4H), 7.47(s, 1H), 7.01 (dd, J=6.7, 4.5 Hz, 1H), 4.59 (p, J=6.8 Hz, 1H), 1.76 (s,3H), 1.37 (d, J=7.0 Hz, 3H).

Example 125.2-Amino-N-[1-(8-chloro-1-cyano-3-methyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.6-Acetyl-8-chloro-3-methyl-5-phenylimidazo[1,5-a]pyridine-1-carbonitriletrifluoroacetate salt

A degassed mixture of1-(8-chloro-1-iodo-3-methyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanone(125 mg, 0.304 mmol, from Example 124, Step 1), zinc cyanide (180 mg,1.5 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct(32 mg, 0.030 mmol), and2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (25 mg, 0.061mmol) in DMF (5.5 mL) and water (27 μL) was heated in the microwave to160° C. for 45 minutes. The mixture was diluted with acetonitrile andfiltered. The product was purified by preparative HPLC/MS (pH=2). Yield:0.020 g, 21%. LCMS calculated for C₁₇H₁₃ClN₃O monoisotopic (M+H)⁺:m/z=310.1; found. 310.0.

Step 2.2-Amino-N-[1-(8-chloro-1-cyano-3-methyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Using6-acetyl-8-chloro-3-methyl-5-phenylimidazo[1,5-a]pyridine-1-carbonitriletrifluoroacetate salt, Steps 11 and 12 of Example 26 were followed toafford the title compound. Yield: 4.3 mg. LCMS calculated forC₂₄H₂₀ClN₈O monoisotopic (M+H)⁺: m/z=471.1; found. 471.1. ¹H NMR (400MHz, d₆-DMSO) δ 8.91 (dd, J=6.7, 1.5 Hz, 1H), 8.55 (dd, J=4.5, 1.5 Hz,1H), 8.04 (d, J=6.3 Hz, 1H), 7.84-7.74 (m, 1H), 7.68-7.53 (m, 4H), 7.58(s, 1H), 7.01 (dd, J=6.7, 4.5 Hz, 1H), 4.58 (p, J=6.8 Hz, 1H), 1.73 (s,3H), 1.37 (d, J=7.0 Hz, 3H).

Example 126.2-Amino-N-[1-(8-chloro-1-ethynyl-3-methyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(racemic mixture prepared)

Step 1.1-(8-Chloro-1-ethynyl-3-methyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanamine

(Trimethylsilyl)acetylene (72 μL, 0.51 mmol, Aldrich) and triethylamine(92 μL, 0.66 mmol) were added to a degassed mixture of1-(8-chloro-1-iodo-3-methyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanone(30. mg, 0.073 mmol, from Example 124, Step 1),tetrakis(triphenylphosphine)palladium(0) (5.1 mg, 0.0044 mmol) andcopper(I) iodide (1.4 mg, 0.0073 mmol) in DMF (1.0 mL). The reactionmixture was heated in the microwave to 100° C. for 30 minutes. Uponcooling, saturated NaHCO₃ solution was added. The mixture was dilutedwith water and extracted with EtOAc. The organic extract was washed withwater, followed by brine, dried over Na₂SO₄, filtered and concentrated.The residue was dissolved in methanol (2.0 mL), and ammonium acetate(84.5 mg, 1.10 mmol) and sodium cyanoborohydride (23 mg, 0.36 mmol) wereadded. The reaction vessel was sealed and heated to 65° C. overnight.The product was purified by preparative HPLC/MS (pH =10). Yield: 5.0 mg22%. LCMS calculated for C₁₈H₁₇ClN₃ monoisotopic (M+H)⁺: m/z=310.1;found. 310.1.

Step 2.2-Amino-N-[1-(8-chloro-1-ethynyl-3-methyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(racemic mixture prepared)

Using1-(8-chloro-1-ethynyl-3-methyl-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanamine(5.0 mg, 0.016 mmol), Step 12 of Example 26 was followed to provide thetitle compound. Yield: 0.8 mg. LCMS calculated for C₂₅H₂₁ClN₇Omonoisotopic (M+H)⁺: m/z=470.1; found. 470.1. ¹H NMR (400 MHz, d₆-DMSO)δ 8.92 (dd, J=6.7, 1.6 Hz, 1H), 8.55 (dd, J=4.3, 1.6 Hz, 1H), 8.01 (d,J=6.6 Hz, 1H), 7.80-7.73 (m, 1H), 7.65-7.53 (m, 4H), 7.16 (s, 1H), 7.01(dd, J=6.6, 4.6 Hz, 1H), 6.42 (s, 2H), 4.55 (p, J=7.5 Hz, 1H), 2.08 (s,1H), 1.69 (s, 3H), 1.35 (d, J=6.9 Hz, 3H).

Example 127.2-Amino-N-[1-(8-chloro-5-pyridin-3-ylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1. Methyl 5-chloro-6-cyano-2,3′-bipyridine-3-carboxylate

The product was prepared by the method of Example 118, Step 1, using3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.0 g, 19 mmol,Aldrich) and methyl 2,5-dichloro-6-cyanonicotinate (3.0 g, 13 mmol, fromExample 26, Step 3). Yield: 3.6 g, 93%. LCMS calculated forC₁₃H₉ClN₃O₂monoisotopic (M+H)⁺: m/z=274.1; found 274.0.

Step 2. Methyl 6-(aminomethyl)-5-chloro-2,3′-bipyridine-3-carboxylate

A degassed solution of methyl5-chloro-6-cyano-2,3′-bipyridine-3-carboxylate (3.3 g, 12 mmol) in MeOH(200 mL) was treated with Raney® Nickel 2800 (1.0 mL of a slurry inwater, Aldrich) and stirred under 1 atm H₂ (provided by a balloon)overnight. The reaction mixture was filtered through Celite® and thefiltrate was concentrated in vacuo. The product was used without furtherpurification. Yield: 3.2 g, 86%. LCMS calculated forC₁₃H₁₃ClN₃O₂monoisotopic (M+H)⁺: m/z=278.1; found 278.0.

Step 3. Methyl8-chloro-5-pyridin-3-ylimidazo[1,5-a]pyridine-6-carboxylate

Formic acid (19 mL) and acetic anhydride (5.0 mL) were combined andstirred for 40 minutes at room temperature, then the mixture was addeddropwise into a 0° C. solution of methyl6-(aminomethyl)-5-chloro-2,3′-bipyridine-3-carboxylate (3.2 g, 10. mmol)in DCM (57 mL). The cooling bath was removed, and the mixture was warmedto room temperature and stirred for 30 minutes after reaching roomtemperature. Volatiles were removed in vacuo. The residue was dissolvedin phosphoryl chloride (12 mL, 130 mmol). After stirring for 1 hour atroom temperature, the mixture was poured slowly onto crushed ice and theaqueous solution was neutralized by the addition of Na₂CO₃. The aqueousmixture was extracted twice with DCM. The combined organic extracts weredried over Na₂SO₄, filtered and concentrated. The product was purifiedby flash chromatography (0-5% MeOH in DCM). Yield: 1.92 g, 64%. LCMScalculated for C₁₄H₁₁ClN₃O₂ monoisotopic (M+H)⁺: m/z=288.1; found 288.1.

Step 4.2-Amino-N-[1-(8-chloro-5-pyridin-3-ylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Using methyl8-chloro-5-pyridin-3-ylimidazo[1,5-a]pyridine-6-carboxylate, Steps 8-12of Example 26 were followed to afford the title compound. LCMScalculated for C₂₁H₁₈ClN₈O monoisotopic (M+H)⁺: m/z=433.1; found 433.1.¹H NMR (400 MHz, d6-DMSO) δ 9.13-9.08 (m, 0.5H), 8.95-8.85 (m, 2.5H),8.58-8.54 (m, 1H), 8.42-8.37 (m, 0.5H), 8.26-8.21 (m, 0.5H), 8.19 (s,1H), 8.07-8.02 (m, 1H), 7.85 (dd, J=7.8, 5.1 Hz, 0.5H), 7.83 (s, 1H),7.80 (dd, J=7.7, 5.2 Hz, 0.5H), 7.44 (s, 0.5H), 7.44 (s, 0.5H),7.04-6.99 (m, 1H), 4.65 (h, J=6.9 Hz, 1H), 1.49 (d, J=7.0 Hz, 1.5H),1.45 (d, J=7.0 Hz, 1.5H).

Example 128.2-Amino-N-[1-(8-chloro-1-cyano-5-pyridin-3-ylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.1-(8-Chloro-1-iodo-5-pyridin-3-ylimidazo[1,5-a]pyridin-6-yl)ethanone

1-(8-Chloro-5-(pyridin-3-yl)imidazo[1,5-a]pyridin-6-yl)ethanone wasprepared by treating methyl8-chloro-5-pyridin-3-ylimidazo[1,5-a]pyridine-6-carboxylate (Example127, Step 3) with the methods of Example 26, Steps 8 through 10 toafford 1-(8-chloro-5-(pyridin-3-yl)imidazo[1,5-a]pyridin-6-yl)ethanone.1-(8-Chloro-5-(pyridin-3-yl)imidazo[1,5-a]pyridin-6-yl)ethanone (0.300g, 1.10 mmol) was iodinated by the method of Example 124, Step 1 toprovide the title compound. Yield: 0.44 g, 100%. LCMS calculated forC_(H)H_(I0)C1IN₃Omonoisotopic (M+H)⁺: m/z=398.0; found 397.9.

Step 2.6-Acetyl-8-chloro-5-(pyridin-3-yl)imidazo[1,5-a]pyridine-1-carbonitrile

Using1-(8-chloro-1-iodo-5-pyridin-3-ylimidazo[1,5-a]pyridin-6-ypethanone, themethod of Example 164, Steps 2 through 5 were followed to afford thetitle compound. LCMS calculated for C₁₅H₁₀ClN₄O monoisotopic (M+H)⁺:m/z=297.1; found 297.0.

Step 3.2-Amino-N-[1-(8-chloro-1-cyano-5-pyridin-3-ylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Starting with6-acetyl-8-chloro-5-(pyridin-3-yl)imidazo[1,5-a]pyridine-1-carbonitrile(19 mg, 0.064 mmol), the methods of Steps 11 and 12 of Example 26 werefollowed to afford the title compound. Yield: 3.5 mg. LCMS calculatedfor C₂₂H₁₇ClN₉O monoisotopic (M+H)⁺: m/z=458.1; found 458.1. ¹H NMR (400MHz, d₆-DMSO) δ 9.05-9.03 (m, 0.5H), 8.93 (dd, J=2.7, 1.6 Hz, 0.5H),8.91 (dd, J=2.7, 1.7 Hz, 0.5H), 8.86 (dd, J=4.9, 1.5 Hz, 1H), 8.82-8.80(m, 0.5H), 8.57-8.54 (m, 1H), 8.33-8.27 (m, 0.5H), 8.17-8.10 (m, 0.5H),8.07 (d, J=6.2 Hz, 0.5H), 8.06 (d, J=6.1 Hz, 0.5H), 7.97 (s, 1H), 7.80(s, 0.5H), 7.78 (s, 0.5H), 7.76 (dd, J=7.8, 4.9 Hz, 0.5H), 7.70 (dd,J=7.6, 5.2 Hz, 0.5H), 7.04-7.00 (m, 1H), 4.73-4.59 (m, 1H), 1.49 (d,J=7.0 Hz, 1.5H), 1.44 (d, J=7.1 Hz, 1.5H).

Example 129.2-Amino-N-[1-(8-chloro-1-methyl-5-pyridin-3-ylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.1-(8-Chloro-1-methyl-5-pyridin-3-ylimidazo[1,5-a]pyridin-6-yl)ethanone

A degassed mixture of1-(8-chloro-1-iodo-5-pyridin-3-ylimidazo[1,5-a]pyridin-6-yl)ethanone (25mg, 0.063 mmol, Example 128, Step 1), trimethylboroxine (11 μL, 0.078mmol, Aldrich), K₂CO₃ (35 mg, 0.25 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1), (5.1 mg, 0.0063 mmol) in DMF (1.0 mL) washeated to 140° C. in the microwave for 30 minutes. Upon cooling to roomtemperature, the mixture was diluted with MeCN, filtered and purified bypreparative HPLC/MS (pH=10). Yield: 2.6 mg, 14%. LCMS calculated forC₁₅H₁₃ClN₃O monoisotopic (M+H)⁺: m/z=286.1; found 286.1.

Step 2.2-Amino-N-[1-(8-chloro-1-methyl-5-pyridin-3-ylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Using1-(8-chloro-1-methyl-5-pyridin-3-ylimidazo[1,5-a]pyridin-6-ypethanone(2.6 mg, 0.0091 mmol), the procedures in Example 26, Steps 11 and 12were followed to afford the title compound. Yield: 2.7 mg. LCMScalculated for C₂₂H₂₀ClN₈O monoisotopic (M+H)⁺: m/z=447.1; found 447.2.¹H NMR (400 MHz, CD₃OD) δ 9.19-9.14 (m, 0.5H), 8.93-8.85 (m, 1H),8.82-8.77 (m, 1.5H), 8.69 (dd, J=6.7, 1.4 Hz, 1H), 8.53 (dd, J=4.4, 1.5Hz, 1H), 8.51-8.48 (m, 0.5H), 8.23 (d, J=8.0 Hz, 0.5H), 7.91-7.81 (m,1H), 7.48 (s, 1H), 6.98 (dd, J=6.7, 4.7 Hz, 1H), 4.76-4.65 (m, 1H), 2.87(s, 3H), 2.02 (s, 3H), 1.55 (d, J=7.2 Hz, 1.5H), 1.53 (d, J=7.2 Hz,1.5H).

Example 130.2-Amino-N-{1-[8-chloro-5-(1H-pyrazol-3-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1. 2,5-Dichloro-N-methoxy-N-methylnicotinamide

2,5-Dichloronicotinic acid (25.0 g, 120 mmol, Combi-Blocks) in DMF (500mL) was treated with N,N-diisopropylethylamine (110 mL, 630 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (30. g, 160mmol), 1-hydroxy-7-azabenzotriazole (5 g, 40 mmol) andN,O-dimethylhydroxylamine hydrochloride (19 g, 200 mmol). The reactionwas stirred for 60 hours. Water was added and the mixture was extractedwith two portions of EtOAc. The combined organic extracts were washedwith water, followed by brine, dried over Na₂SO₄, filtered andconcentrated. The product was used without further purification. Yield:30.6 g, 81%. LCMS calculated for C₈H₉Cl₂N₂O₂monoisotopic (M+H)⁺:m/z=235.0; found 234.9.

Step 2. 2,5-Dichloro-N-methoxy-N-methylnicotinamide 1-oxide

Urea hydrogen peroxide addition compound (21 g, 220 mmol) was added to2,5-dichloro-N-methoxy-N-methylnicotinamide (24.7 g, 105 mmol) in DCM(200 mL) at 0° C. This was followed by the dropwise addition oftrifluoroacetic anhydride (30 mL, 210 mmol). The reaction mixture wasallowed to slowly warm to room temperature and stir overnight. A Na₂S₂O₃solution was added and the mixture was stirred for 10 minutes. SaturatedNaHCO₃ solution (200 mL) was then carefully added. Additional solidNa₂CO₃ was added to achieve pH=8. The layers were separated and theaqueous layer was extracted with DCM. The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Theproduct was purified by flash chromatography (0-70% EtOAc in hexanes).Yield: 14.9 g, 57%. LCMS calculated for C₈H₉Cl₂N₂O₃ monoisotopic (M+H)⁺:m/z=251.0; found 250.9.

Step 3. 2,5-Dichloro-6-cyano-N-methoxy-N-methylnicotinamide

2,5-Dichloro-N-methoxy-N-methylnicotinamide 1-oxide (14.9 g, 59.3 mmol)in MeCN (250 mL) and triethylamine (26 mL, 190 mmol) was treated withtrimethylsilyl cyanide (20. mL, 150 mmol) dropwise at room temperature.The mixture was then heated to 70° C. for 6.5 hours. The reaction wascooled to room temperature and poured into K₂CO₃ solution. Afterstirring for 20 minutes, the layers were separated and the aqueous layerwas extracted with two portions of EtOAc. The combined organic extractswere dried over Na₂SO₄, filtered and concentrated. The product waspurified by flash chromatography (25-65% EtOAc in hexanes). Yield: 13.4g, 87%. LCMS calculated for C₉H₈Cl₂N₃O₂ monoisotopic (M+H)⁺: m/z=260.0;found 259.9.

Step 4. 6-(Aminomethyl)-2,5-dichloro-N-methoxy-N-methylnicotinamide

To a degassed solution of2,5-dichloro-6-cyano-N-methoxy-N-methylnicotinamide (4000. mg, 15.38mmol) in formic acid (120 mL) was rapidly added Raney® Nickel 2800 (28mL of a slurry in water). The reaction mixture was stirred at roomtemperature for 5 minutes. The reaction mixture was filtered throughCelite® and the filter aid was then washed with MeOH and water, and allsolvents were removed in vacuo from the filtrate. To the residue wasadded water, and the mixture was washed once with EtOAc to removeimpurities. A 6N sodium hydroxide solution was added to the aqueouslayer to achieve pH=10. Formed solids were again removed by filtrationthrough Celite®, and the filter aid was washed with excess EtOAc. Thelayers of the biphasic filtrate were separated, and the aqueous layerwas saturated with NaCl and extracted with three additional portions ofEtOAc. The combined organic extracts were dried over Na₂SO₄, filtered,and concentrated. The product was used without further purification.Yield: 2.6 g (64%). LCMS calculated for C₉H₁₂Cl₂N₃O₂monoisotopic (M+H)⁺:m/z=264.0; found 264.0.

Step 5.2,5-Dichloro-6-[(formylamino)methyl]-N-methoxy-N-methylnicotinamide

Formic acid (24 mL, 630 mmol) and acetic anhydride (6.2 mL, 65 mmol)were stirred together for 40 minutes at room temperature, and themixture was added dropwise into a solution of6-(aminomethyl)-2,5-dichloro-N-methoxy-N-methylnicotinamide (5.37 g,20.3 mmol) in DCM (130 mL) at 0° C. The mixture was stirred at 0° C. for30 minutes, then allowed to slowly warm to room temperature overnight.Volatiles were removed in vacuo at ambient temperature, and the productwas used without further purification. LCMS calculated forC₁₀H₁₂Cl₂N₃O₃monoisotopic (M+H)⁺: m/z=292.0; found 292.0.

Step 6.5,8-Dichloro-N-methoxy-N-methylimidazo[1,5-a]pyridine-6-carboxamide

2,5-Dichloro-6-[(formylamino)methyl]-N-methoxy-N-methylnicotinamide(5.94 g, 20.3 mmol) in THF (300 mL) was treated with phosphoryl chloride(13 mL, 140 mmol) at room temperature for 7 hours. The reaction mixturewas poured slowly onto crushed ice and the pH of the cold aqueousmixture was adjusted to pH=8 by the addition of solid K₂CO₃. Some of theTHF was removed in vacuo. The organic layer was then separated and solidNaCl was added to saturate the aqueous layer. The aqueous layer was thenextracted with DCM (3×). All organic extracts were combined, washed withbrine, dried over Na₂SO₄, filtered and concentrated. The product waspurified by flash chromatography (0-100% EtOAc/hexanes). Yield: 4.35 g,78.0%. LCMS calculated for C₁₀H₁₀Cl₂N₃O₂ monoisotopic (M+H)⁺: m/z=274.0;found 274.0.

Step 7. 1-(5,8-Dichloroimidazo[1,5-a]pyridin-6-yl)ethanone

3.0 M Methylmagnesium chloride in THF (8 mL, 20 mmol) was added to asolution of5,8-dichloro-N-methoxy-N-methylimidazo[1,5-a]pyridine-6-carboxamide (2.1g, 7.7 mmol) in THF (40 mL) at 0° C. The reaction was stirred for 2hours, and then allowed to gradually warm to room temperature. Thereaction was then cooled to 0° C. and was quenched by the addition of1.0 N HCl (8 mL, 8 mmol). The mixture was diluted with water, andextracted twice with EtOAc. The combined organic extracts were washedwith brine, dried over MgSO₄, filtered, and concentrated. The productwas purified by flash chromatography (0-80% EtOAc in hexanes). Yield:1.45 g, 81%. LCMS calculated for C₉H₇Cl₂N₂O monoisotopic (M+H)⁺:m/z=229.0; found 229.1.

Step 8.1-{8-Chloro-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]imidazo[1,5-a]pyridin-6-yl}ethanone

A degassed mixture of 1-(5,8-dichloroimidazo[1,5-a]pyridin-6-yl)ethanone(20 mg, 0.086 mmol),1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(36 mg, 0.13 mmol, Aldrich), cesium fluoride (39 mg, 0.26 mmol) andbis(triphenylphosphine)palladium(II) chloride (6.1 mg, 0.0086 mmol) inwater (0.15 mL) and 1,4-dioxane (0.4 mL) was heated to 80° C. for 3hours, then at 70° C. overnight. Additional1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(24 mg, 0.086 mmol), cesium fluoride (39 mg, 0.26 mmol) andbis(triphenylphosphine)palladium(II) chloride (6.1 mg, 0.0086 mmol) wereadded and heating was continued at 85° C. for 3 hours. The mixture wascooled to room temperature and saturated NaHCO₃ solution was added. Themixture was extracted with EtOAc (3×). The combined organic extractswere dried over Na₂SO₄, filtered and concentrated. The product waspurified by flash chromatography (0-80% EtOAc in hexanes). Yield: 14 mg,47%. LCMS calculated for C₁₇H₁₈ClN₄O₂ monoisotopic (M+H)⁺: m/z=345.1;found 345.1.

Step 9.2-Amino-N-{1-[8-chloro-5-(1H-pyrazol-3-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Using1-{8-chloro-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]imidazo[1,5-a]pyridin-6-yl}ethanone(14 mg, 0.041 mmol), Steps 11 and 12 of Example 26 were followed toprovide the title compound. Yield: 3.9 mg. LCMS calculated forC₁₉H₁₇ClN₉O monoisotopic (M+H)⁺: m/z=422.1; found 422.1. ¹H NMR (400MHz, d₆-DMSO) δ 8.91 (dd, J=6.7, 1.5 Hz, 1H), 8.57 (dd, J=4.5, 1.5 Hz,1H), 8.29 (s, 1H), 8.11-8.01 (m, 2H), 7.64 (s, 1H), 7.27 (s, 1H), 7.01(dd, J=6.7, 4.5 Hz, 1H), 6.88 (d, J=2.3 Hz, 1H), 5.11 (p, J=7.1 Hz, 1H),1.52 (d, J=7.0 Hz, 3H).

Examples 131-138

The following Examples of Table 10 were prepared as in Example 130,using appropriately substituted boronic esters, boronic acids orstannanes as starting materials in Step 8. NMR data for the compounds ofTable 10 are provided in Table 10a.

TABLE 10

Ex. No. Name R = LCMS 131 2-Amino-N-(1-{8-chloro-5-[5-(methyl-sulfonyl)pyridin-3-yl]imidazo[1,5-a]-pyridin-6-yl}-ethyl)pyrazolo[1,5-a]- pyrimidine-3-carboxamide trifluoro-acetate salt (racemic mixture prepared)

Calculated for C₂₂H₂₀ClN₈O₃S monoisotopic (M + H)⁺: m/z = 511.1; found:511.1 132 2-Amino-N-(8-chloro-5-{6-[(methyl-amino)carbonyl]pyridin-3-yl}imidazo-[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5- a]pyrimidine-3-carboxamidetrifluoro- acetate salt (racemic mixture prepared)

Calculated for C₂₃H₂₁ClN₉O₂ monoisotopic (M + H)⁺: m/z = 490.1; found:490.1 133 2-Amino-N-[1-(8-chloro-5-pyridin-2-ylimidazo[1,5-a]pyridin-6-yl)ethyl]- pyrazolo[1,5-a]pyrimidine-3-carbox-amide trifluoroacetate salt (racemic mixture prepared)

Calculated for C₂₁H₁₈ClN₈O monoisotopic (M + H)⁺: m/z = 433/1; found433.1 134 2-Amino-N-{1-[8-chloro-5-(5-meth-oxypyridin-3-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine- 3-carboxamide trifluoroacetatesalt (racemic mixture prepared)

Calculated for C₂₂H₂₀ClN₈O₂ monoisotopic (M + H)⁺: m/z = 463.1; found:463.1 135 2-Amino-N-[1-(8-chloro-5-{4-[(methyl-amino)sulfonyl]phenyl}imidazo[1,5- a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]-pyrimidine-3-carboxamide trifluoro- acetate salt (racemic mixtureprepared)

Calculated for C₂₃H₂₂ClN₈O₃S isotopic (M + H)⁺: m/z = 525.1; found:525.1 136 2-Amino-N-(1-{8-chloro-5-[4-(methyl-sulfonyl)phenyl]imidazo[1,5-a]pyridin-6-yl}ethyl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide trifluoroacetatesalt (racemic mixture prepared)

Calculated for C₂₃H₂₁ClN₇O₃S monoisotopic (M + H)⁺: m/z = 510.1; found:510.1 137 2-Amino-N-{1-[8-chloro-5-(5-cyano-pyridin-3-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3- carboxamide trifluoroacetate salt(racemic mixture prepared)

Calculated for C₂₂H₁₇ClN₉O monoisotopic (M + H)⁺: m/z = 458.1; found:458.1 138 2-Amino-N-[1-(8-chloro-5-pyrazin-2-ylimidazo[1,5-a]pyridin-6-yl)ethyl]- pyrazolo[1,5-a]pyrimidine-3-carbox-amide trifluoroacetate salt (racemic mixture prepared)

Calculated for C₂₀H₁₇ClN₉O monoisotopic (M + H)⁺: m/z = 434.1; found:434.1

TABLE 10a Ex. No. ¹H NMR 131 ¹H NMR (400 MHz, d₆-DMSO) δ 9.33 (d, J =1.9 Hz, 0.5H), 9.31 (d, J = 2.2 Hz, 0.5H), 9.29 (d, J = 2.2 Hz, 0.5H),9.12 (d, J = 1.9 Hz, 0.5H), 8.93-8.88 (m, 1H), 8.76 (t, J = 2.0 Hz,0.5H), 8.64 (t, J = 2.0 Hz, 0.5H), 8.57-8.53 (m, 1H), 8.14 (s, 0.5H),8.13 (s, 0.5H), 8.03 (d, J = 6.6 Hz, 0.5H), 8.01 (d, J = 6.9 Hz, 0.5H),7.74 (s, 0.5H), 7.73 (s, 0.5H), 7.45 (s, 0.5H), 7.38 (s, 0.5H), 7.01(dd, J = 6.5, 4.8 Hz, 1H), 4.63 (p, J = 6.8 Hz, 0.5H), 4.58 (p, J = 6.9Hz, 0.5H), 3.42 (s, 1.5H), 3.42 (s, 1.5H), 1.51 (d, J = 7.0 Hz, 1.5H),1.46 (d, J = 7.0 Hz, 1.5H) 132 ¹H NMR (400 MHz, d₆-DMSO) δ 9.11-9.06 (m,0.5H), 9.05-9.00 (m, 0.5H), 8.93-8.86 (m, 1.5H), 8.80-8.78 (m, 0.5H),8.56-8.53 (m, 0.5H), 8.51-8.49 (m, 0.5H), 8.43-8.38 (m, 0.5H), 8.32-8.18(m, 1.5H), 8.00 (d, J = 6.3 Hz, 0.5H), 7.94 (d, J = 6.5 Hz, 0.5H), 7.90(s, 0.5H), 7.89 (s, 0.5H), 7.63 (s, 1H), 7.33 (s, 0.5H), 7.32 (s, 0.5H),7.04-6.97 (m, 1H), 6.41 (br s, 2H), 4.65 (p, J = 7.0 Hz, 1H), 2.88 (d, J= 4.0 Hz, 1.5H), 2.87 (d, J = 4.0 Hz, 1.5H), 1.50 (d, J = 7.0 Hz, 1.5H),1.45 (d, J = 7.0 Hz, 1.5H). 133 ¹H NMR (400 MHz, d₆-DMSO) δ 8.91 (dd, J= 6.7, 1.5 Hz, 1H), 8.87-8.85 (m, 1H), 8.56 (dd, J = 4.5, 1.5 Hz, 1H),8.13 (td, J = 7.7, 1.6 Hz, 1H), 8.03 (d, J = 6.5 Hz, 1H), 8.00 (d, 1H),7.99 (s, 1H), 7.67 (s, 1H), 7.65-7.61 (m, 1H), 7.33 (s, 1H), 7.01 (dd, J= 6.7, 4.5 Hz, 1H), 4.88 (p, J = 6.8 Hz, 1H), 1.47 (d, J = 7.0 Hz, 3H)134 ¹H NMR (400 MHz, CD₃OD) δ 8.69 (dd, J = 6.8, 1.2 Hz, 1H), 8.65-8.62(m, 1H), 8.60- 8.57 (m, 0.5H), 8.56-8.51 (m, 1H), 8.50-8.47 (m, 0.5H),8.47-8.43 (m, 0.5H), 8.36- 8.34 (m, 0.5H), 8.07-8.04 (m, 0.5H), 8.03 (s,1H), 7.70-7.64 (m, 0.5H), 7.52 (s, 0.5H), 7.51 (s, 0.5H), 7.00-6.96 (m,1H), 4.93-4.87 (m, 1H), 4.00 (s, 1.5H), 3.84 (s, 1.5H), 1.57 (d, J = 7.0Hz, 1.5H), 1.56 (d, J = 7.1 Hz, 1.5H) 135 ¹H NMR (400 MHz, d₆-DMSO) δ8.92 (dd, J = 6.7, 1.6 Hz, 1H), 8.55 (dd, J = 4.5, 1.6 Hz, 1H),8.09-7.99 (m, 4H), 7.97 (s, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.73 (s, 1H),7.66 (q, J = 4.9 Hz, 1H), 7.36 (s, 1H), 7.01 (dd, J = 6.7, 4.5 Hz, 1H),4.68 (p, J = 7.1 Hz, 1H), 2.54 (d, J = 4.9 Hz, 3H), 1.45 (d, J = 7.0 Hz,3H) 136 ¹H NMR (400 MHz, d₆-DMSO) δ 8.92 (dd, J = 6.7, 1.5 Hz, 1H), 8.56(dd, J = 4.5, 1.5 Hz, 1H), 8.25 (dd, J = 8.1, 1.8 Hz, 1H), 8.17 (dd, J =8.1, 1.7 Hz, 1H), 8.12 (dd, J = 8.0, 1.2 Hz, 1H), 8.04 (d, J = 6.3 Hz,1H), 7.95 (s, 1H), 7.90 (dd, J = 8.1, 1.3 Hz, 1H), 7.73 (s, 1H), 7.36(s, 1H), 7.01 (dd, J = 6.7, 4.5 Hz, 1H), 4.67 (p, J = 6.6 Hz, 1H), 3.36(s, 3H), 1.46 (d, J = 7.0 Hz, 3H) 137 ¹H NMR (400 MHz, d₆-DMSO) δ9.28-9.24 (m, 1.5H), 9.06 (d, J = 2.1 Hz, 0.5H), 8.93 (dd, J = 2.9, 1.8Hz, 0.5H), 8.91 (dd, J = 3.0, 1.7 Hz, 0.5H), 8.76 (t, J = 2.0 Hz, 0.5H),8.67 (t, J = 2.0 Hz, 0.5H), 8.55 (dd, J = 4.4, 1.6 Hz, 1H), 7.99 (d, J =6.2 Hz, 1H), 7.97 (s, 1H), 7.62 (s, 1H), 7.35 (s, 0.5H), 7.31 (s, 0.5H),7.03-6.99 (m, 1H), 4.64-4.53 (m, 1H), 1.51 (d, J = 7.0 Hz, 1.5H), 1.45(d, J = 7.0 Hz, 1.5H) 138 ¹H NMR (400 MHz, d₆-DMSO) δ 9.20 (s, 1H), 8.94(dd, J = 2.3, 1.6 Hz, 1H), 8.91 (dd, J = 6.8, 1.6 Hz, 1H), 8.88 (d, J =2.5 Hz, 1H), 8.55 (dd, J = 4.5, 1.5 Hz, 1H), 8.08 (s, 1H), 8.01 (d, J =6.4 Hz, 1H), 7.65 (s, 1H), 7.35 (s, 1H), 7.01 (dd, J = 6.7, 4.5 Hz, 1H),4.80 (p, J = 6.8 Hz, 1H), 1.50 (d, J = 7.0 Hz, 3H)

Example 139.2-Amino-N-{1-[8-chloro-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1. Methyl 5-chloro-6-cyano-2-(1H-pyrazol-4-yl)nicotinate

A degassed mixture of methyl 2,5-dichloro-6-cyanonicotinate (1.5 g, 6.5mmol, Example 26, Step 3), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(3.8 g, 13 mmol, Aldrich), cesium fluoride (3.0 g, 19 mmol) andbis(triphenylphosphine)palladium(II) chloride (0.27 g, 0.39 mmol) inwater (11.4 mL) and 1,4-dioxane (29.6 mL) was heated to 80° C. for 3hours, then overnight at 70° C. Only the Boc-deprotected product wasobserved. Upon cooling to room temperature, saturated NaHCO₃ was added,and the mixture was extracted with EtOAc. The EtOAc extract was driedover Na₂SO₄, filtered and concentrated. The product was purified byflash chromatography (0-50% EtOAc in hexanes). Yield: 1.4 g, 82%. LCMScalculated for C₁₁H₈ClN₄O₂ monoisotopic (M+H)⁺: m/z=263.0; found: 263.1.

Step 2. teat-Butyl{3-[({1-[8-chloro-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}amino)carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}carbamate

Using methyl 5-chloro-6-cyano-2-(1H-pyrazol-4-yl)nicotinate, Example 27,Steps 2-9 were followed to afford the title compound. LCMS calculatedfor C₂₄H₂₅ClN₉O₃ monoisotopic (M+H)⁺: m/z=522.2; found: 522.1.

Step 3.2-Amino-N-{1-[8-chloro-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

The method of Example 27, Step 10 was followed, starting with tert-butyl{3-[({1-[8-chloro-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}amino)carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}carbamate(10. mg, 0.019 mmol) to afford the title compound. Yield: 8.5 mg. LCMScalculated for C₁₉H₁₇ClN₉O monoisotopic (M+H)⁺: m/z=422.1; found: 422.1.¹ H NMR (400 MHz, d₆-DMSO) δ 8.91 (dd, J=6.7, 1.5 Hz, 1H), 8.56 (dd,J=4.5, 1.6 Hz, 1H), 8.32 (s, 1H), 8.16 (s, 1H), 8.07 (d, J=6.6 Hz, 1H),7.73 (s, 1H), 7.31 (s, 1H), 7.01 (dd, J=6.7, 4.5 Hz, 1H), 4.98 (p, J=6.8Hz, 1H), 1.46 (d, J=7.0 Hz, 3H).

Example 140.2-Amino-N-{1-[8-chloro-5-(1-methyl-1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

tert-Butyl{3[({1-[8-chloro-5-1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}amino)carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}carbamate(12 mg, 0.023 mmol, Example 139, Step 2) in DMF (0.20 mL) was treatedwith Cs₂CO₃ (15 mg, 0.046 mmol) and MeI (0.10 mL of a stock solutionprepared from adding 0.16 mL MeI to 10 mL of DMF). The reaction wasstirred for 15 minutes, then was diluted with DCM, filtered, andconcentrated. The residue was stirred with TFA (0.1 mL) in DCM (0.7 mL)for 2 hours. Volatiles were removed in vacuo and the product waspurified by preparative HPLC/MS (pH=2). Yield: 5.9 mg. LCMS calculatedfor C₂₀H₁₉ClN₉O monoisotopic (M+H)⁺: m/z=436.1; found: 436.1. ¹H NMR(400 MHz, d₆-DMSO) δ 8.92 (dd, J=6.7, 1.4 Hz, 1H), 8.57 (dd, J=4.5, 1.4Hz, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 8.07 (d, J=6.5 Hz, 1H), 7.92 (s,1H), 7.72 (s, 1H), 7.29 (s, 1H), 7.02 (dd, J=6.7, 4.6 Hz, 1H), 5.00 (p,J=6.6 Hz, 1H), 4.00 (s, 3H), 1.47 (d, J=7.0 Hz, 3H).

Example 141.2-Amino-N-(1-{8-chloro-5-[4-(methylsulfonyl)piperazin-1-yl]imidazo[1,5-a]pyridin-6-yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1. tert-Butyl4-[5-chloro-6-cyano-3-(methoxycarbonyl)pyridin-2-yl]piperazine-1-carboxylate

A mixture of methyl 2,5-dichloro-6-cyanonicotinate (370 mg, 1.6 mmol,Example 26, Step 3), tert-butyl piperazine-1-carboxylate (300 mg, 2mmol, Aldrich) and Cs₂CO₃ (1 g, 3 mmol) in acetonitrile (3 mL) washeated to 70° C. for 1 hour. Upon cooling, the reaction mixture waspartitioned between EtOAc and water. The organic layer was washed withbrine, dried over MgSO₄, filtered and concentrated. The product waspurified by flash chromatography (0-50% EtOAc in hexanes). Yield: 0.45g, 74%. LCMS calculated for C₁₇H₂₂ClN₄O₄ monoisotopic (M+H)⁺: m/z=381.1;found 381.1.

Step 2. teat-Butyl4-[6-(aminomethyl)-5-chloro-3-(methoxycarbonyl)pyridin-2-yl]pperazine-1-carboxylate

tert-Butyl4-[5-chloro-6-cyano-3-(methoxycarbonyl)pyridin-2-yl]piperazine-1-carboxylate(450 mg, 1.2 mmol) in methanol (10 mL) was treated with Raney® Nickel2800 (200 μL of a slurry in water) and stirred under H₂ at 20 psi for 2hours. The reaction mixture was filtered and solvent was removed invacuo. The product was used without further purification. Yield: 0.40 g,90%. LCMS calculated for C₁₇H₂₆ClN₄O₄monoisotopic (M+H)⁺: m/z=385.2;found 385.1.

Step 3. Methyl8-chloro-5-piperazin-1-ylimidazo[1,5-a]pyridine-6-carboxylate

Formic acid (3.5 mL) and acetic anhydride (0.90 mL) were stirred for 40minutes at room temperature, then the mixture was added dropwise into a0° C. solution of tert-butyl4-[6-(aminomethyl)-5-chloro-3-(methoxycarbonyl)pyridin-2-yl]piperazine-1-carboxylate(720 mg, 1.9 mmol) in DCM (10. mL). The mixture was stirred for 50minutes at 0° C., then warmed to room temperature and stirred overnight.Solvents were removed in vacuo and the residue was dissolved inphosphoryl chloride (6 mL, 60 mmol) and heated to 75° C. for 1 hour.Upon cooling to room temperature, the mixture was poured into ice andsaturated NaHCO₃ was added to neutralize to pH=7. The mixture wasextracted with DCM. The combined organic extracts were washed withbrine, dried over MgSO₄, filtered and concentrated. The product was usedwithout further purification. Yield: 0.22 g, 40%. LCMS calculated forC₁₃H₁₆ClN₄O₂monoisotopic (M+H)⁺: m/z=295.1; found 295.0.

Step 4. Methyl5-[4-(tert-butoxycarbonyl)piperazin-1-yl]-8-chloroimidazo[1,5-a]pyridine-6-carboxylate

di-tert-Butyldicarbonate (380 mg, 1.7 mmol) was added to a mixture ofmethyl 8-chloro-5-piperazin-1-ylimidazo[1,5-a]pyridine-6-carboxylate(220 mg, 0.75 mmol) and NaHCO₃ (380 mg, 4.5 mmol) in THF (9 mL) andwater (6 mL). The reaction was stirred overnight, then concentrated invacuo. The residue was partitioned between EtOAc and water. The organiclayer was washed with brine, dried over MgSO₄, filtered andconcentrated. The product was purified by flash chromatography (0-100%EtOAc in hexanes). Yield: 0.20 g, 70%. LCMS calculated for C₁₈H₂₄ClN₄O₄monoisotopic (M+H)⁺: m/z=395.1; found 395.2.

Step 5. tert-Butyl4-(6-acetyl-8-chloroimidazo[1,5-a]pyridin-5-yl)piperazine-1-carboxylate

Using methyl5-[4-(tert-butoxycarbonyl)piperazin-1-yl]-8-chloroimidazo[1,5-a]pyridine-6-carboxylate,Steps 8-10 of Example 26 were followed to afford the title compound.LCMS calculated for C₁₈H₂₄ClN₄O₃ monoisotopic (M+H)⁺: m/z=379.2; found379.2.

Step 6. 1-(8-Chloro-5-piperazin-1-ylimidazo[1,5-a]pyridin-6-yl)ethanonehydrochloride salt

4.0 M Hydrogen chloride in dioxane (2 mL, 8 mmol) was added to asolution of tert-butyl4-(6-acetyl-8-chloroimidazo[1,5-a]pyridin-5-yl)piperazine-1-carboxylate(70 mg, 0.2 mmol) in 1,4-dioxane (2 mL). The reaction was stirred for 30minutes, and the volatiles were removed in vacuo. The product was usedwithout further purification. Yield: 0.060 g, 100%. LCMS calculated forC₁₃H₁₆ClN₄O monoisotopic (M+H)⁺: m/z=279.1; found 279.2.

Step 7.1-{8-Chloro-5-[4-(methylsulfonyl)piperazin-1-yl]imidazo[1,5-a]pyridin-6-yl}ethanone

Methanesulfonyl chloride (11 μL, 0.14 mmol) was added to a solution of1-(8-chloro-5-piperazin-1-ylimidazo[1,5-a]pyridin-6-yl)ethanonehydrochloride salt (30 mg, 0.1 mmol) and N,N-diisopropylethylamine (80μL, 0.5 mmol) in DCM (2 mL). The reaction was stirred for 30 minutes andvolatiles were removed in vacuo. The product was used without furtherpurification. Yield: 0.030 g, 90%. LCMS calculated for C₁₄H₁₈ClN₄O₃Smonoisotopic (M+H)⁺: m/z=357.1; found 357.1.

Step 8.2-Amino-N-(1-{8-chloro-5-[4-(methylsulfonyl)piperazin-1-yl]imidazo[1,5-a]pyridin-6-yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Using1-{8-chloro-5-[4-(methylsulfonyl)piperazin-1-yl]imidazo[1,5-a]pyridin-6-yl}ethanone(30. mg, 0.08 mmol), Steps 11 and 12 of Example 26 were followed toafford the title compound. Yield: 3.0 mg. LCMS calculated forC₂₁H₂₅ClN₉O₃S monoisotopic (M+H)⁺: m/z=518.1; found 518.1. ¹H NMR (600MHz, d₆-DMSO) δ 8.91 (dd, J=6.7, 1.6 Hz, 1H), 8.79 (s, 1H), 8.56 (dd,J=4.5, 1.6 Hz, 1H), 8.09 (d, J=6.9 Hz, 1H), 7.63 (s, 1H), 7.15 (s, 1H),7.01 (dd, J=6.7, 4.5 Hz, 1H), 6.45 (br s, 2H), 5.48 (p, J=6.9 Hz, 1H),3.59-3.26 (m, 8H), 2.99 (s, 3H), 1.54 (d, J=7.0 Hz, 3H).

Example 142.2-Amino-N-[1-(8-chloro-5-pyrrolidin-1-ylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1. Methyl 5-chloro-6-cyano-2-pyrrolidin-1-ylnicotinate

A mixture of methyl 2,5-dichloro-6-cyanonicotinate (300 mg, 1 mmol,Example 26, Step 3), pyrrolidine (90 mg, 1 mmol), and Cs₂CO₃ (800 mg, 2mmol) in acetonitrile (2 mL) was heated to 70° C. for 1 hour. Uponcooling, the reaction mixture was partitioned between EtOAc and water,and the organic layer was washed with brine, dried over MgSO₄, filteredand concentrated. The product was purified by flash chromatography(0-100% EtOAc in hexanes).Yield: 300 mg, 90%. LCMS calculated forC₁₂H₁₃ClN₃O₂monoisotopic (M+H)⁺: m/z=266.1; found: 266.1.

Step 2. 1-(8-Chloro-5-pyrrolidin-1-ylimidazo[1,5-a]pyridin-6-yl)ethanone

Using methyl 5-chloro-6-cyano-2-pyrrolidin-1-ylnicotinate, Steps 2through 7 of Example 27 were followed to afford the title compound. LCMScalculated for C₁₃H₁₅ClN₃O monoisotopic (M+H)⁺: m/z=264.1; found: 264.1.

Step 3.1-(8-Chloro-5-pyrrolidin-1-ylimidazo[1,5-a]pyridin-6-yl)ethanamine(racemicmixture prepared)

A mixture of1-(8-chloro-5-pyrrolidin-1-ylimidazo[1,5-a]pyridin-6-ypethanone (80 mg,0.3 mmol), ammonium acetate (440 mg, 5.7 mmol), and sodiumcyanoborohydride (120 mg, 1.9 mmol) in methanol (12 mL) was heated to65° C. overnight in a sealed reaction vessel. Upon cooling, water andmethanol were added and the mixture was filtered and purified bypreparative HPLC/MS (pH=10). Yield: 8.0 mg, 10%. LCMS calculated forCI3H18C1N4 monoisotopic (M+H)^(±): m/z=265.1; found: 265.1.

Step 4.2-Amino-N-[1-(8-chloro-5-pyrrolidin-1-ylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Using 1-(8-chloro-5-pyrrolidin-1-ylimidazo[1,5-a]pyridin-6-yl)ethanamine(racemic) (6.0 mg, 0.02 mmol), the method of Example 26, Step 12 wasfollowed to afford the title compound. Yield: 3.0 mg. LCMS calculatedfor C₂₀H₂₂ClN₈O monoisotopic (M+H)⁺: m/z=425.2; found: 425.3. ¹H NMR(400 MHz, CD₃OD) δ 9.20 (s, 1H), 8.69 (dd, J=6.8, 1.5 Hz, 1H), 8.55 (dd,J=4.5, 1.5 Hz, 1H), 8.03 (s, 1H), 7.40 (s, 1H), 6.98 (dd, J=6.8, 4.5 Hz,1H), 5.43 (q, J =6.9 Hz, 1H), 3.69-3.54 (m, 2H), 3.49-3.38 (m, 2H),2.25-2.16 (m, 4H), 1.63 (d, J=7.0 Hz, 3H).

Example 143.2-Amino-N-{1-[8-chloro-5-(4-methoxypiperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(racemic mixture prepared)

Step 1.1-[8-Chloro-5-(4-methoxypiperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethanamine(racemic mixture prepared)

Titanium tetraisopropoxide (300 μL, 1 mmol) was added to1-[8-chloro-5-(4-methoxypiperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethanone(50 mg, 0.2 mmol, prepared by the method of Example 142, Steps 1 and 2,using 4-methoxy piperidine in Step 1) in 2.0 M ammonia in ethanol (800μL, 2 mmol) and the reaction mixture was heated to 65° C. in a sealedvial overnight. The reaction mixture was then cooled to 0° C. and sodiumborohydride (9.6 mg, 0.26 mmol) was added. After stirring for 1 hour,the reaction was quenched by the addition of 1N NH₄OH. Formed solidswere removed by filtration and washed with acetonitrile. The filtratewas evaporated to dryness, reconstituted with EtOAc, dried using MgSO₄,filtered and concentrated. The product was used without furtherpurification. Yield: 40 mg, 30%. LCMS calculated for C₁₅H₂₂ClN₄Omonoisotopic (M+H)⁺: m/z=309.1; found: 309.1.

Step 2. tert-Butyl{3-[({1-[8-chloro-5-(4-methoxypiperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}amino)carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}carbamate(racemic mixture prepared)

Using1-[8-chloro-5-(4-methoxypiperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethanamine(20 mg, 0.06 mmol), the method of Example 27, Step 9 was followed toafford the title compound. The racemic product was used without furtherpurification. LCMS calculated for C₂₇H₃₄ClN₈O₄ monoisotopic (M+H)⁺:m/z=569.2; found: 569.2.

Step 3.2-Amino-N-{1-[8-chloro-5-(4-methoxypiperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(racemic mixture prepared)

Using tert-butyl{3-[({1-[8-chloro-5-(4-methoxypiperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}amino)carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}carbamate(racemic), the method of Example 27, Step 10 was used to afford thetitle compound. The product was purified using the pH=10 method. Yield:7 mg over the two steps. LCMS calculated for C₂₂H₂₆ClN₈O₂ monoisotopic(M+H)⁺: m/z=469.2; found: 469.2. ¹H NMR (400 MHz, d₆-DMSO) δ 8.92 (dd,J=6.7, 1.4 Hz, 1H), 8.58-8.55 (m, 1H), 8.52 (s, 0.6H), 8.32 (s, 0.4H),8.10-8.03 (m, 1H), 7.46 (s, 1H), 7.05 (s, 0.4H), 7.03-6.99 (m, 1.6H),6.42 (s, 2H), 5.53-5.44 (m, 0.6H), 5.45-5.35 (m, 0.4H), 3.55-3.09 (m,8H), 2.11-1.96 (m, 2H), 1.80-1.60 (m, 2H), 1.54 (d, J=7.0 Hz, 1.2H),1.52 (d, J=7.0 Hz, 1.8H).

Examples 144-145.

Examples 144-145 in Table 11 were prepared according to the method ofExample 143. NMR data for the compounds of Table 11 are provided inTable 11a.

TABLE 11

Ex. No. Name R = LCMS 144 2-Amino-N-{1-[8-chloro-5-(3-methoxy-pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine- 3-carboxamide trifluoroacetatesalt (mixture of diastereomers prepared)

Calculated for C₂₁H₂₄ClN₈O₂ monoisotopic (M + H)+: m/z = 455.2; found:455.2 145 2-Amino-N-[1-(8-chloro-5-morpholin-4-ylimidazo[1,5-a]pyridin-6-yl)ethyl]-pyrazolo[1,5-a]pyrimidine-3-carbox- amide trifluoroacetate salt (racemicmixture prepared)

Calculated for C₂₀H₂₂ClN₈O₂ monoisotopic (M + H)+: m/z = 441.2; found:441.2

TABLE 11a Ex. No. ¹H NMR 144 ¹H NMR (400 MHz, CD₃OD) δ 9.33-9.24 (m,2H), 8.72-8.64 (m, 2H), 8.58-8.53 (m, 2H), 7.99 (s, 2H), 7.35 (s, 1H),7.33 (s, 1H), 7.01-6.94 (m, 2H), 5.58-5.47 (m, 2H), 4.26-4.16 (m, 2H),3.81-3.39 (m, 8H), 3.47 (s, 3H), 3.46 (s, 3H), 2.39-2.12 (m, 4H), 1.62(d, J = 7.0 Hz, 3H), 1.60 (d, J = 6.9 Hz, 3H) 145 ¹H NMR (400 MHz,d₆-DMSO) δ 8.91 (dd, J = 6.7, 1.6 Hz, 1H), 8.88 (s, 1H), 8.56 (dd, J =4.5, 1.6 Hz, 1H), 8.09 (d, J = 6.8 Hz, 1H), 7.72 (s, 1H), 7.20 (s, 1H),7.01 (dd, J = 6.7, 4.5 Hz, 1H), 5.53 (p, J = 6.4 Hz, 1H), 3.99-3.68 (m,4H), 3.55-3.38 (m, 2H), 3.33 (d, J = 13.1 Hz, 1H), 3.26-3.09 (m, 1H),1.55 (d, J = 6.9 Hz, 3H)

Example 146.2-Amino-N-{1-[8-chloro-5-(4-hydroxypiperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

1.0 M Boron tribromide in DCM (188 μL, 0.188 mmol) was added portionwiseto a solution of teat-butyl{3-[({1-[8-chloro-5-(4-methoxypiperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}amino)carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}carbamate(25 mg, 0.044 mmol, Example 143, Step 2) in DCM (2 mL) at −78° C. Thereaction was warmed to room temperature and was quenched by the additionof saturated NaHCO₃. The mixture was extracted with EtOAc. The combinedorganic extracts were dried over MgSO₄, filtered, and concentrated.Removal of the Boc protecting group occurred under conditions of thereaction. The product was purified by preparative HPLC/MS (pH=2). Yield:2 mg. LCMS calculated for C₂₁H₂₄ClN₈O₂ monoisotopic (M+H)⁺: m/z=455.2;found: 455.2.

Example 147.2-Amino-N-{1-[5-(4-bromopiperidin-1-yl)-8-chloroimidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

The title compound was isolated as a byproduct of the reaction describedin Example 146. Yield: 3 mg. LCMS calculated for C₂₁H₂₃BrClN₈Omonoisotopic (M+H)⁺: m/z=517.1; found: 517.1. ¹H NMR (400 MHz, d₆-DMSO)δ 8.94-8.90 (m, 1H), 8.72 (s, 0.6H), 8.65 (s, 0.4H), 8.57 (dd, J=4.5,1.6 Hz, 1H), 8.11-8.05 (m, 1H), 7.67 (s, 0.4H), 7.60 (s, 0.6H), 7.16 (s,0.4H), 7.11 (s, 0.6H), 7.02 (dd, J=6.7, 4.4 Hz, 1H), 5.56-5.48 (m,0.6H), 5.43-5.34 (m, 0.4H), 4.73-4.57 (m, 1H), 3.56-3.12 (m, 4H),2.43-2.05 (m, 4H), 1.56 (d, J=3.7 Hz, 1.2H), 1.54 (d, J=3.4 Hz, 1.8H).

Example 148

Example 148 in Table 12 was prepared by the method of Example 146, usingExample 144 as the starting material (Boc-deprotected).

TABLE 12

Ex. No. Name R = LCMS 148 2-Amino-N-{1-[8-chloro-5-(3-hydroxy-pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine- 3-carboxamide trifluoroacetatesalt (mixture of diastereomers prepared)

Calculated for C₂₀H₂₂ClN₈O₂ monoisotopic (M + H)⁺: m/z = 441.2; found:441.1

Example 149.2-Amino-N-{1-[8-chloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.1-[8-Chloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethanone

A mixture of 1-(5,8-dichloroimidazo[1,5-a]pyridin-6-yl)ethanone (30.0mg, 0.131 mmol, Example 130, Step 7), 1,2,5-thiadiazepane 1,1-dioxide(0.051 g, 0.17 mmol, 1:1 by weight with TEA prepared as described in WO2014/009295) and N,N-diisopropylethylamine (0.068 mL, 0.39 mmol) in MeCN(1.0 mL) was heated to 70° C. for 1 hour. Additional 1,2,5-thiadiazepane1,1-dioxide (0.051 g, 0.17 mmol) was added and heating was continued for16 hours. Volatiles were removed in vacuo and the product was purifiedby flash chromatography (0-100% EtOAc/hexanes). Yield: 0.022 g, 49%.LCMS calculated for C₁₃H₁₆O₃N₄SCl monoisotopic (M+H)⁺: m/z=343.1; found343.0.

Step 2.1-[8-Chloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethanamine(racemicmixture prepared)

A mixture of1-[8-chloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethanone(22 mg, 0.064 mmol) in 2.0 M NH₃ in EtOH (3 mL, 6 mmol) was treated withtitanium tetraisopropoxide (100 μL, 0.4 mmol) and the reaction mixturewas heated to 65° C. overnight. The reaction mixture was cooled to 0° C.and sodium borohydride (7 mg, 0.2 mmol) was added. The reaction wasstirred at 0° C. for 1 hour. Additional sodium borohydride (4 mg, 1mmol) was added and the reaction mixture was stirred for 4 hours. Adilute solution of NH₄OH was added (0.2 mL). The mixture was filteredthrough a PTFE syringe filter and the filter was rinsed with MeCN (10mL). The filtrate was concentrated. The residue was partitioned betweenEtOAc and water and the layers were separated. The aqueous portion wasextracted with two additional portions of EtOAc. The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The product was used without further purification andtheoretical yield was assumed. LCMS calculated for C₁₃H₁₉O₂N₅SClmonoisotopic (M+H)⁺: m/z=344.1; found 344.0.

Step 3. tert-Butyl{3-[({1-[8-chloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}amino)carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}carbamate(racemicmixture prepared)

N,N-Diisopropylethylamine (30 μL, 0.2 mmol) was added to a mixture of1-[8-chloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethanamine(22 mg, 0.064 mmol),2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (21 mg, 0.077 mmol, J&W Pharmlab) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (36 mg, 0.096 mmol) in DMF (2.5 mL). After stirringfor 1 hour, the reaction was diluted with water and extracted withEtOAc. The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated to afford product which was used withoutfurther purification. Theoretical yield was assumed. LCMS calculated forC₂₅H₃₁ClN₉O₅S monoisotopic (M+H)⁺: m/z=604.2, found 604.3.

Step 4.2-Amino-N-{1-[8-chloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(racemic mixture prepared)

To tert-butyl{3-[({1-[8-chloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}amino)carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}carbamate(0.039 g, 0.064 mmol) in DCM (2 mL) was added TFA (2 mL). The solutionwas stirred for 1 hour. Volatiles were removed in vacuo. The residue wasdissolved in MeOH/H₂O/MeCN and purified by preparative HPLC/MS (pH=2) toafford product as the trifluoroacetate salt. Yield: 30 mg. LCMScalculated for C₂₀H₂₃O₃N₉SCl monoisotopic (M+H)⁺: m/z=504.1; found504.1. ¹H NMR (400 MHz, CD₃OD) δ 9.43 (s, 0.5H), 9.34 (s, 0.5H), 8.69(dd, J=6.8, 1.6 Hz, 1H), 8.58-8.53 (m, 1H), 7.98 (s, 0.5H), 7.97 (s,0.5H), 7.37 (s, 0.5H), 7.35 (s, 0.5H), 6.98 (dd, J=6.7, 4.6 Hz, 1H),5.63 (q, J=7.0, 6.2 Hz, 0.5H), 5.54 (q, J=7.1, 6.0 Hz, 0.5H), 4.14-3.32(m, 8H), 1.65 (d, J=3.6 Hz, 1.5H), 1.63 (d, J=3.6 Hz, 1.5H).

Examples 150-153

Examples 150-153 in Table 13 were prepared by the method of Example 149,using appropriately substituted commercially available amines in Step 1.NMR data for representative compounds of Table 13 are provided in Table13a.

TABLE 13

Ex. No. Name R = LCMS 150 2-Amino-N-(1-{8-chloro-5-[(3S,5S)-3,5-dihydroxypiperidin-1-yl]imidazo[1,5-a]-pyridin-6-yl}ethyl)pyrazolo[1,5-a]- pyrimidine-3-carboxamide trifluoro-acetate salt (single isomer prepared via separation of diastereomers-peak2, second to elute during preparative HPLC/MS at pH = 2)

Calculated for C₂₁H₂₄ClN₈O₃, monoisotopic (M + H)⁺: m/z = 471.2; found:471.1 151 2-Amino-N-{1-[8-chloro-5-(1,1-dioxido-1,4-thiazepan-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3- carboxamide trifluoroacetatesalt (racemic mixture prepared)

Calculated for C₂₁H₂₄ClN₈O₃S monoisotopic (M + H)⁺: m/z = 503.1: found:503.2 152 2-Amino-N-(1-{8-chloro-5-[(3S)-3-hydroxypiperidin-1-yl]imidazo[1,5-a]-pyridin-6-yl}ethyl)pyrazolo[1,5-a]- pyrimidine-3-carboxamide trifluoro-acetate salt (mixture of two diastereo- mers prepared)

Calculated for C₂₁H₂₄ClN₈O₂: monoisotopic (M + H)⁺: m/z = 455.2; found:455.2 153 2-Amino-N-{1-[8-chloro-5-(4-cyano-piperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3- carboxamide trifluoroacetate salt(racemic mixture prepared)

Calculated for C₂₂H₂₃ClN₉O monoisotopic (M + H)⁺: m/z = 464.2; found:464.2

TABLE 13a Ex. No. ¹H NMR 150 ¹H NMR (400 MHz, d₆-DMSO) δ 9.00 (s, 1H),8.92 (dd, J = 6.7, 1.4 Hz, 1H), 8.57 (dd, J = 4.5, 1.4 Hz, 1H), 8.08 (d,J = 6.6 Hz, 1H), 7.59 (s, 1H), 7.10 (s, 1H), 7.01 (dd, J = 6.7, 4.5 Hz,1H), 5.43 (p, J = 6.7 Hz, 1H), 4.10-3.98 (m, 1H), 3.48-3.41 (m, 1H),3.16-3.05 (m, 4H), 2.00-1.87 (m, 1H), 1.68-1.58 (m, 1H), 1.51 (d, J =6.8 Hz, 3H) 151 ¹H NMR (400 MHz, CD₃OD) δ 9.46 (s, 1H), 8.74-8.69 (m,1H), 8.60-8.56 (m, 1H), 7.99 (s, 1H), 7.38 (s, 1H), 7.01 (dd, J = 6.8,4.5 Hz, 1H), 5.56 (p, J = 6.9 Hz, 1H), 4.10-3.36 (m, 8H), 2.42-2.16 (m,2H), 1.68 (d, J = 6.8 Hz, 1.5H), 1.66 (d, J = 6.7 Hz, 1.5H)

Example 154.2-Amino-N-{1-[8-chloro-5-(4-methyl-3-oxopiperazin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.4-[6-(1-Aminoethyl)-8-chloroimidazo[1,5-a]pyridin-5-yl]-1-methylpiperazin-2-one

A mixture of4-(6-acetyl-8-chloroimidazo[1,5-a]pyridin-5-yl)-1-methylpiperazin-2-one(7.0 mg, 0.016 mmol, prepared as in Example 149, Step 1 using1-methylpiperazin-2-one instead of 1,2,5-thiadiazepane 1,1-dioxide),ammonium acetate (26 mg, 0.34 mmol) and sodium cyanoborohydride (7.2 mg,0.11 mmol) was heated to 70° C. overnight. Upon cooling to roomtemperature, saturated NaHCO₃ (5 mL) was added. The mixture was thenextracted twice with 10% iPrOH in DCM. The combined organic extractswere dried over Na₂SO₄, filtered and concentrated. The product was usedwithout further purification, and theoretical yield was assumed. LCMScalculated for C₁₄H₁₉ClN₅O monoisotopic (M+H)⁺: m/z=308.1; found: 308.1.

Step 2.2-Amino-N-{1-[8-chloro-5-(4-methyl-3-oxopperazin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Using4-[6-(1-aminoethyl)-8-chloroimidazo[1,5-a]pyridin-5-yl]-1-methylpiperazin-2-one,the method of Example 26, Step 12 was followed to afford the titlecompound. Yield: 4.0 mg. LCMS calculated for C₂₁H₂₃ClN₉O₂ monoisotopic(M+H)⁺: m/z=468.2; found: 468.2. ¹H NMR (400 MHz, d₆-DMSO) δ 9.05 (s,0.5H), 8.98 (s, 0.5H), 8.95-8.87 (m, 1H), 8.60-8.53 (m, 1H), 8.14-8.05(m, 1H), 7.79 (s, 0.5H), 7.76 (s, 0.5H), 7.24 (s, 0.5H), 7.23 (s, 0.5H),7.06-6.99 (m, 1H), 5.49-5.33 (m, 1H), 4.34-3.39 (m, 6H), 2.98 (s, 3H),1.55 (d, J=6.5 Hz, 1.5H), 1.54 (d, J=6.5 Hz, 1.5H).

Examples 155A-157

Examples 155A-157 in Table 14 were prepared by the method of Example154, using amines prepared as described in Tetrahedron Letters, 36(4),549-52; 1995, or derived therefrom using methods known to one skilled inthe art. NMR data for representative compounds of Table 14 are providedin Table 14a.

TABLE 14

Ex. No. Name R = LCMS 155A 2-Amino-N-(1-{8-chloro-5-[(3R,5R)-3,5-dihydroxypiperidin-1-yl]imidazo- [1,5-a]pyridin-6-yl}ethyl)pyrazolo-[1,5-a]]pyrimidine-3-carboxamide trifluoroacetate salt (mixture of twodiastereomers prepared)

Calculated for C₂₁H₂₄ClN₈O₃ monoisotopic (M + H)⁺: m/z = 471.2: found:471.1 155B 2-Amino-N-(1-{8-chloro-5-[(3R,5S)-3,5-dihydroxypiperidin-1-yl]imidazo- [1,5-a]pyridin-6-yl}ethyl)pyrazolo-[1,5-a]pyrimidine-3-carboxamide trifluoroacetate salt (mixture of twodiastereomers prepared)

Calculated for C₂₁H₂₄ClN₈O₃ monoisotopic (M + H)⁺: m/z = 471 2: found:471.2 156  2-Amino-N-(1-{8-chloro-5-[(3R,5R)-3-fluoro-5-hydroxypiperidin-1-yl]- imidazo[1,5-a]pyridin-6-yl}ethyl)-pyrazolo[1,5-a]pyrimidine-3-carbox- amide trifluoroacetate salt (mixtureof two diastereomers prepared)

Calculated for C₂₁H₂₃ClFN₈O₂ monoisotopic (M + H)⁺: m/z = 473.2; found:473.1 157  2-Amino-N-(1-{8-chloro-5-[(3S,5R)-3-cyano-5-hydroxypiperidin-1-yl]- imidazo[1,5-a]pyridin-6-yl}ethyl)-pyrazolo[1,5-a]pyrimidine-3-carbox- amide trifluoroacetate salt (mixtureof two diastereomers prepared)

Calculated for C₂₂H₂₃ClN₉O₂ monoisotopic (M + H)⁺: m/z = 480.2: found:480.1

TABLE 14a Ex. No. ¹H NMR 156 ¹H NMR (400 MHz, CD₃OD) δ 9.90-9.72 (m,0.5H), 9.29-9.13 (m, 0.5H), 8.71-8.65 (m, 1H), 8.57-8.51 (m, 1H), 7.41(s, 0.5H), 7.39 (s, 0.5H), 7.02-6.93 (m, 1H), 5.51- 5.41 (m, 1H),5.18-5.07 (m, 0.5H), 5.06-4.97 (m, 0.5H), 4.27-4.15 (m, 1H), 3.88- 3.21(m, 4H), 2.50-1.69 (m, 2H), 1.63 (d, J = 7.0 Hz, 1.5H), 1.60 (d, J = 7.0Hz, 1.5H)

Example 158.2-Amino-N-(1-(8-chloro-5-(1,1-dioxido-1,4-thiazepan-4-yl)-3-methylimidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.5,8-Dichloro-N-methoxy-N,3-dimethylimidazo[1,5-a]pyridine-6-carboxamide

To 6-(aminomethyl)-2,5-dichloro-N-methoxy-N-methylnicotinamide (700 mg,3 mmol, from Example 130, Step 4) and N,N-diisopropylethylamine (1.2 mL,6.6 mmol) in DMF (6.4 mL) was added acetic anhydride (380 μL, 4.0 mmol).After 30 minutes, saturated NaHCO₃ solution was added and the mixturewas extracted with EtOAc. The combined organic extracts were washed withwater, then brine, dried over Na₂SO₄, filtered and concentrated. Thecrude product was stirred at room temperature with phosphoryl chloride(7.1 mL, 76 mmol) for one hour. Phosphoryl chloride was removed on therotovap and crushed ice was added to the flask. Solid Na₂CO₃ was addedto achieve pH=7. The mixture was extracted with EtOAc. The organicextract was dried over Na₂SO₄, filtered and concentrated. The productwas used without further purification. Yield: 550 mg, 70%. LCMScalculated for C₁₁H₁₂Cl₂N₃O₂monoisotopic (M+H)⁺: m/z=288.0; found 288.1.

Step 2. 1-(5,8-Dichloro-3-methylimidazo[1,5-a]pyridin-6-yl)ethanone

3.0 M Methylmagnesium chloride in THF (4 mL, 10 mmol) was added to asolution of5,8-dichloro-N-methoxy-N,3-dimethylimidazo[1,5-a]pyridine-6-carboxamide(1.1 g, 3.8 mmol) in THF (20 mL) at 0° C. After 2 hours, the bath wasremoved and the mixture was warmed to room temperature. The reactionmixture was re-cooled to 0° C. and 3.0 M Methylmagnesium chloride in THF(1.26 mL, 3.8 mmol) was added. The cooling bath was removed and themixture was stirred at room temperature for 1 hour. The mixture wasre-cooled to 0° C. and 1.0 N HCl (2 mL, 2 mmol) was added. The mixturewas diluted with water and extracted with EtOAc. The organic extract waswashed with brine, dried over MgSO₄, filtered and concentrated. Theproduct was purified by flash chromatography (0-100% EtOAc in hexanes).Yield: 0.80 g, 90%. LCMS calculated for C₁₀H₉Cl₂N2O monoisotopic (M+H)⁺:m/z=243.0; found 243.1.

Step 3.1-(8—Chloro-5-(1,1-dioxido-1,4-thiazepan-4-yl)-3-methylimidazo[1,5-a]pyridin-6-yl)ethan-1-one

1-(5,8-Dichloro-3-methylimidazo[1,5-a]pyridin-6-ypethanone (20 mg, 0.09mmol), 1,4-thiazepane 1,1-dioxide HCl salt (30 mg, 0.2 mmol, Enamine)and N,N-diisopropylethylamine (40 μL, 0.3 mmol) in MeCN (1 mL) washeated to 150° C. in the microwave for 3 hours. Upon cooling, thereaction mixture was partitioned between EtOAc and water. The organiclayer was dried over MgSO₄, filtered and concentrated. The product waspurified by flash chromatography (0-100% EtOAc in hexanes). Yield: 25mg, 80%. LCMS calculated for C₁₅H₁₉ClN₃O₃S monoisotopic (M+H)⁺:m/z=356.1; found 356.1.

Step 4.1-[8-Chloro-5-(1,1-dioxido-1,4-thiazepan-4-yl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethanamine(racemicmixture prepared)

Titanium tetraisopropoxide (200 μL, 0.5 mmol) was added to a mixture of1-[8-chloro-5-(1,1-dioxido-1,4-thiazepan-4-yl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethanone(30 mg, 0.09 mmol) in 2.0 M ammonia in ethanol (3 mL, 6 mmol). Thereaction was stirred at 65° C. in a sealed tube overnight. Sodiumborohydride (10 mg, 0.3 mmol) was added and the mixture was stirred for1 hour. A 1N ammonium hydroxide solution was added and a precipitateformed that was filtered off and rinsed with acetonitrile. The crudeproduct obtained on evaporation of the filtrate was partitioned betweenwater and EtOAc. The organic layer was washed with brine, dried overMgSO4, filtered and concentrated to afford product which was usedwithout further purification. Yield: 20 mg, 60%. LCMS calculated forCI5H22C1N402S monoisotopic (M+H)⁺: m/z=357.1; found 357.1.

Step 5.2-Amino-N-(1-(8-chloro-5-(1,1-dioxido-1,4-thiazepan-4-yl)-3-methylimidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Starting with1-[8-chloro-5-(1,1-dioxido-1,4-thiazepan-4-yl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethanamine(racemic) (20 mg, 0.06 mmol), the method of Example 26, Step 12 was usedto provide the title compound. Yield: 5 mg. LCMS calculated forC₂₂H₂₆ClN₈O₃S monoisotopic (M+H)⁺: m/z=517.2; found 517.1. ¹H NMR (400MHz, CD₃OD) δ 8.69 (dd, J=6.8, 1.3 Hz, 1H), 8.58-8.54 (m, 1H), 8.00 (s,1H), 7.36 (s, 0.4H), 7.33 (s, 0.6H), 6.98 (dd, J=6.4, 4.7 Hz, 1H), 5.59(q, J=6.6 Hz, 0.4H), 5.51 (q, J=7.0 Hz, 0.6H), 4.18-3.34 (m, 8H), 3.07(s, 1.8H), 3.05 (s, 1.2H), 2.60-2.20 (m, 2H), 1.66 (d, J=6.8 Hz, 3H).

Example 159.2-Amino-N-{1-[8-chloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)-1-(trifluoromethypimidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

To2-amino-N-{1-[8-chloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (0.023 g, 0.037 mmol, from Example 149) and zincbis(trifluoromethanesulfinate) (0.037 g, 0.11 mmol, Aldrich) in CHCl₃(0.6 mL) and H₂O (0.150 mL) at 0° C. was added tert-butyl hydroperoxide(0.025 mL, 0.19 mmol). The reaction mixture was warmed to roomtemperature and stirred overnight. The reaction was worked up bypartition between EtOAc and water. The aqueous layer was extracted withtwo further portions of EtOAc. The combined organic extracts were driedover Na₂SO₄, filtered and concentrated. DMF and MeOH were used toreconstitute the residue, which was purified by preparative HPLC/MS(pH=2). Yield: 2 mg. LCMS calculated for C₂₁H₂₂ClF₃N₉O₃S monoisotopic(M+H)⁺: m/z=572.1; found 572.2. ¹H NMR (400 MHz, CD₃OD) δ 8.68 (dd,J=6.8, 1.4 Hz, 1H), 8.66 (s, 0.5H), 8.63 (s, 0.5H), 8.57-8.54 (m, 1H),7.38 (s, 0.5H), 7.34 (s, 0.5H), 6.98 (dd, J=6.8, 4.7 Hz, 1H), 5.70 (q,J=6.8 Hz, 0.5H), 5.63 (q, J=6.9 Hz, 0.5H), 4.17-3.34 (m, 8H), 1.63 (d,J=7.4 Hz, 1.5H), 1.61 (d, J=7.3 Hz, 1.5H).

Example 160.2-Amino-N-{(1S)-1-[1,8-dichloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (scalemic mixture prepared)

Step 1. 1-(1,5,8-Trichloroimidazo[1,5-a]pyridin-6-yl)ethanone

1-(5,8-Dichloroimidazo[1,5-a]pyridin-6-yl)ethanone (0.300 g, 1.31 mmol,from Example 130, Step 7) in DMF (10 mL) was treated withN-chlorosuccinimide (0.19 g, 1.4 mmol). The reaction was stirredovernight. An additional portion of N-chlorosuccinimide (0.040 g, 0.29mmol) was added and the reaction was stirred for 1 hour. The reactionmixture was diluted with water and extracted with three portions ofEtOAc. The combined organic extracts were washed with water, dried overNa₂SO₄, filtered and concentrated. The crude product was purified byflash chromatography (O-75% EtOAc/hexanes). Yield: 0.24 g, 70%. LCMScalculated for C₉H₆ON₂Cl₃ monoisotopic (M+H)⁺: m/z=263.0; found 262.9.

Step 2.1-[1,8-Dichloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethanone

A mixture of 1-(1,5,8-trichloroimidazo[1,5-a]pyridin-6-yl)ethanone (50.0mg, 0.190 mmol), 1,2,5-thiadiazepane 1,1-dioxide (0.074 g, 0.25 mmol,1:1 by weight with TEA, prepared as described in WO2014/009295) andN,N-diisopropylethylamine (0.10 mL, 0.57 mmol) in acetonitrile (1.4 mL)was heated to 70° C. for 2.5 hours. Additional 1,2,5-thiadiazepane1,1-dioxide (0.074 g, 0.25 mmol) was added and heating was continued for2 hours. The reaction was diluted with water and extracted with threeportions of EtOAc. The combined organic extracts were dried over Na₂SO₄,filtered and concentrated. The product was triturated with MeOH toafford a yellow powder. Yield: 0.055 g, 77%. LCMS calculated forC₁₃H₁₅O₃N₄SCl₂monoisotopic (M+H)⁺: m/z=377.0; found 377.0.

Step 3.(1S)-1-[1,8-Dichloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethanaminehydrochloride salt (scalemic mixture prepared)

To a solution of1-[1,8-dichloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethanone(27 mg, 0.072 mmol) and (S)-2-methylpropane-2-sulfinamide (87 mg, 0.72mmol, Aldrich) in 1.1 mL cyclopentyl methyl ether (CPME) was addedtitanium tetraisopropoxide (0.063 mL, 0.21 mmol) and the reactionmixture was heated to 100° C. for 6 hours. Additional CPME (1.5 mL),(S)-2-methylpropane-2-sulfinamide (20 mg, 0.17 mmol) and Ti(OiPr)₄ (30μL, 0.1 mmol) were added and the reaction was heated overnight. A thirdportion of (S)-2-methylpropane-2-sulfinamide (20 mg, 0.17 mmol) andTi(OiPr)₄ (30 μL, 0.1 mmol) were added and heating was continued for 6hours. The reaction mixture was cooled to 0° C. and ethanol (0.5 mL, 8mmol) and sodium borohydride (15 mg, 0.40 mmol, powdered, in oneportion) were added. After 15 minutes, the bath was removed and thereaction mixture was rapidly warmed to ambient temperature. The reactionwas quenched by the dropwise addition of water. The mixture was dilutedwith water and was extracted with three portions of EtOAc. The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated. Theproduct was purified by preparative HPLC/MS (pH=2) and eluentevaporated. The sulfinamide obtained (0.020 g, 0.034 mmol) was dissolvedin MeOH (1.0 mL) and treated with 4.0 M HCl in dioxane (1.0 mL, 4.0mmol). After stirring for 45 minutes, volatiles were removed in vacuo toafford the crude product as the HCl salt, which was used without furtherpurification. Yield: 16 mg. LCMS calculated for C₁₃H₁₈Cl₂N₅O₂Smonoisotopic (M+H)⁺: m/z=378.1; found 378.1.

Step 4.2-Amino-N-{(1S)-1-[1,8-dichloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (scalemic mixture prepared)

N,N-Diisopropylethylamine (20 μL, 0.1 mmol) was added to2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (15 mg, 0.055 mmol, J&W Pharmlab) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (24 mg, 0.063 mmol) in DMF (1 mL). After stirringfor 10 minutes,(1S)-1-[1,8-dichloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethanamine(16 mg, 0.042 mmol) in DMF (1 mL) was added dropwise. The reaction wasstirred for 1 hour. The reaction was diluted with water and extractedwith EtOAc. The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated. Trifluoroacetic Acid (1 mL) was added to asolution of the crude product in DCM (1 mL). After stirring for 1 hour,volatiles were removed in vacuo and the product was purified bypreparative HPLC/MS (pH=2). Yield: 6 mg. LCMS calculated forC₂₀H₂₂O₃N₉SCl₂ (M+H)⁺: m/z=538.1; found 538.0. ¹H NMR (400 MHz, CD₃OD) δ8.67 (dd, J=6.8, 1.6 Hz, 1H), 8.55 (dd, J=4.5, 1.3 Hz, 1H), 8.45 (s,0.5H), 8.42 (s, 0.5H), 7.04 (s, 0.5H), 6.99 (s, 0.5H), 6.97 (dd, J=6.8,4.5 Hz, 1H), 5.68 (q, J=6.9 Hz, 0.5H), 5.60 (q, J=6.9 Hz, 0.5H),4.04-3.32 (m, 8H), 1.60 (d, J=7.5 Hz, 1.5H), 1.58 (d, J=7.3 Hz, 1.5H).

Example 161

Example 161 of Table 15 were prepared by the method of Example 160,using an appropriately substituted amine in Step 2. NMR data for thecompound of Table 15 is provided in Table 15a.

TABLE 15

Ex. No. Name R = LCMS 161 2-Amino-N-{(1S)-1-[1,8-dichloro-5-(5-oxo-1,4-diazepan-1-yl)imidazo- [1,5-a]pyridin-6-yl]ethyl}pyrazolo-[1,5-a]pyrimidine-3-carboxamide trifluoroacetate salt (scalemic mixtureprepared)

Calculated for C₂₁H₂₂Cl₂N₉O₂ monoisotopic (M + H)⁺: m/z = 502.1; found:502.1

TABLE 15a Ex. No. ¹H NMR 161 ¹H NMR (400 MHz, CD₃OD) δ 8.69-8.65 (m,1H), 8.54 (m, J = 3.3 Hz, 1H), 8.44 (s, 0.5H), 8.43 (s, 0.5H), 7.00 (s,0.5H), 6.99 (s, 0.5H), 6.98-6.93 (m, 1H), 5.58-5.50 (m, 1H), 3.71-3.32(m, 6H), 2.96-2.78 (m, 2H), 1.58 (d, J = 6.9 Hz, 3H)

Example 162.2-Amino-N-{1-[1,8-dichloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.1-[8-Chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethanone

A mixture of 1-(5,8-dichloroimidazo[1,5-a]pyridin-6-yl)ethanone (30 mg,0.1 mmol, Example 130, Step 7), N,N-diisopropylethylamine (70 μL, 0.4mmol) and thiomorpholine 1,1-dioxide (40 mg, 0.3 mmol, TCI) in MeCN (1mL) was heated in the microwave to 150° C. for 2 hours. The reactionmixture was partitioned between EtOAc and water and the layers wereseparated. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated. The product was purified by flashchromatography (0-100% EtOAc in hexanes). Yield: 30 mg, 70%. LCMScalculated for C₁₃H₁₅ClN₃O₃S monoisotopic (M+H)⁺: m/z=328.0; found328.1.

Step 2.1-[1,8-Dichloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethanone

N-Chlorosuccinimide (18 mg, 0.13 mmol) was added to1-[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethanone(40 mg, 0.1 mmol) in DMF (1 mL). The reaction was heated to 70° C. for 2hours. Upon cooling to room temperature, the reaction was diluted withEtOAc and water, and the layers were separated. The organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated. Theproduct was purified by flash chromatography (0-100% EtOAc inhexanes).Yield: 30 mg, 80%. LCMS calculated for C₁₃H₁₄Cl₂N₃O₃Smonoisotopic (M+H)⁺: m/z=362.0; found 362.1.

Step 3.1-[1,8-Dichloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethanamine(racemic mixture prepared)

Titanium tetraisopropoxide (100 μL, 0.4 mmol) was added to a mixture of1-[1,8-dichloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethanone(20 mg, 0.06 mmol) in 2.0 M ammonia in ethanol (3 mL, 5 mmol). Thereaction was stirred at 65° C. in a sealed vessel overnight. Thereaction mixture was cooled to 0° C. and sodium borohydride (7 mg, 0.2mmol) was added. When complete, the reaction was quenched by theaddition of 1N NH₄OH solution. The reaction mixture was filtered and thesolid was washed with MeCN. The filtrate was concentrated in vacuo andthe residue was partitioned between water and EtOAc. The organic layerwas washed with brine, dried over MgSO₄, filtered and concentrated toafford product which was used without further purification. Yield: 20mg, 90%. LCMS calculated for C₁₃H₁₇Cl₂N₄O₂S monoisotopic (M+H)⁺:m/z=363.0; found 363.1.

Step 4.2-Amino-N-{1-[1,8-dichloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

N,N-Diisopropylethylamine (30 μL, 0.2 mmol) was added to a mixture of1-[1,8-dichloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethanamine(20 mg, 0.06 mmol),2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (20 mg, 0.07 mmol), andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (34 mg, 0.090 mmol) in DMF (2 mL). After stirringfor 1 hour, the reaction was diluted with water and extracted withEtOAc. The combined organic extracts were washed with brine, dried overMgSO₄, filtered and concentrated. The residue was dissolved in DCM (1mL) and TFA (1 mL) was added. The reaction was stirred for 1 hour andvolatiles were removed in vacuo. The product was purified by preparativeHPLC/MS (pH=2). Yield: 5 mg. LCMS calculated for C₂₀H₂₁Cl₂N₈O₃Smonoisotopic (M+H)⁺: m/z=523.1; found 523.1. ¹H NMR (400 MHz, d₆-DMSO) δ8.92 (dd, J=6.7, 1.4 Hz, 1H), 8.67 (s, 1H), 8.57 (dd, J=4.5, 1.5 Hz,1H), 8.09 (d, J=6.8 Hz, 1H), 7.08 (s, 1H), 7.01 (dd, J=6.7, 4.6 Hz, 1H),6.42 (s, 2H), 5.30 (p, J=6.8 Hz, 1H), 4.07-3.19 (m, 8H), 1.55 (d, J=6.9Hz, 3H).

Example 163.2-Amino-N-{1-[1,8-dichloro-5-(4-cyanopiperidin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

The title compound was prepared by the method of Example 162,substituting piperidine-4-carbonitrile (29 mg, 0.26 mmol, Aldrich) forthe amine and Cs₂CO₃ (100 mg, 0.4 mmol) for the base in Step 1 andperforming the reaction of Step 1 at 70° C. in the microwave for 1 hour.LCMS calculated for C₂₂H₂₂Cl₂N₉O monoisotopic (M+H)⁺: m/z=498.1; found498.1. ¹H NMR (400 MHz, d₆-DMSO) δ 8.94-8.87 (m, 1H), 8.58-8.53 (m, 1H),8.47 (s, 0.5H), 8.42 (s, 0.5H), 8.10-8.01 (m, 1H), 7.05 (s, 1H),7.03-6.98 (m, 1H), 6.42 (br s, 2H), 5.45-5.37 (m, 0.5H), 5.32-5.24 (m,0.5H), 3.59-2.96 (m, 5H), 2.20-1.85 (m, 4H), 1.52 (d, J=7.0 Hz, 3H).

Example 164.2-Amino-N-{1-[8-chloro-1-cyano-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.1-1-[8-Chloro-5-(1,1-dioxidothiomorphohn-4-yl)-1-iodoimidazo[1,5-a]pyridin-6-yl]ethanone

To a solution of1-[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethanone(200 mg, 0.6 mmol, Example 162, Step 1) in DMF (1.6 mL) was addedN-iodosuccinimide (151 mg, 0.671 mmol) and the reaction was stirred for1 hour. The reaction was quenched by the addition of saturated NaHCO₃solution. The mixture was diluted with water and extracted with EtOAc.The extract was washed with water, followed by brine, dried over Na₂SO₄,filtered and concentrated. The product was used without furtherpurification. Yield: 300 mg, 100%. LCMS calculated for C₁₃H₁₄ClIN₃O₃Smonoisotopic (M+H)⁺: m/z=453.9; found 453.9.

Step 2. Methyl6-acetyl-8-chloro-5-(1,1-dioxidothiomorphohn-4-yl)imidazo[1,5-a]pyridine-1-carboxylate

To a mixture of1-[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)-1-iodoimidazo[1,5-a]pyridin-6-yl]ethanone(300 mg, 0.7 mmol) in MeOH (8 mL) and DMF (5 mL) was added triethylamine(0.24 mL, 1.7 mmol) and the mixture was degassed with a stream ofnitrogen for 5 minutes.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (60 mg, 0.07 mmol) was added. The solutionwas saturated with carbon monoxide by bubbling the gas through thereaction subsurface using a CO balloon. The flask was heated to 60° C.for 2 hours under an atmosphere of CO provided by the balloon. Thereaction was cooled to room temperature and stirred overnight. Themixture was partitioned between water and EtOAc. The aqueous layer wasextracted with a further portion of EtOAc. The combined organic extractswere dried over Na₂SO₄, filtered, and concentrated. The product waspurified by flash chromatography (0-100% EtOAc in hexanes). Yield: 0.18g, 70%. LCMS calculated for CI5H17C1N305S monoisotopic (M+H)⁺:m/z=386.1; found 386.1.

Step 3.6-Acetyl-8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridine-1-carboxylicacid

To methyl6-acetyl-8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridine-1-carboxylate(200 mg, 0.5 mmol) in MeOH (10 mL) and THF (10 mL) was added lithiumhydroxide (50 mg, 2 mmol) in water (3 mL). After stirring for 1 hour,additional lithium hydroxide (25 mg, 1.0 mmol) in water (2 mL) was addedand the reaction was stirred for 3 hours. The mixture was concentratedin vacuo to half the original volume. Water was then added and the basicaqueous mixture was washed with EtOAc to remove impurities. The aqueouslayer was then acidified to pH=4 by the addition of 1N HCl. The acidicaqueous mixture was extracted once with EtOAc, and three times with 5%iPrOH in DCM to obtain the desired product. The combined extracts werewashed with brine, dried over MgSO₄, filtered and concentrated. Theproduct was used without further purification. Yield: 60 mg, 30%. LCMScalculated for C₁₄H₁₅ClN₃O₅S monoisotopic (M+H)⁺: m/z=372.0; found372.1.

Step 4.6-Acetyl-8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridine-1-carboxamide

To a mixture of6-acetyl-8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridine-1-carboxylicacid (60 mg, 0.2 mmol), ammonium chloride (20 mg, 0.3 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (100 mg, 0.3 mmol) in DMF (3 mL) was addedN,N-diisopropylethylamine (100 μL, 0.6 mmol). After stirring overnight,the reaction mixture was diluted with EtOAc and washed with water. Thelayers were separated and the aqueous layer was extracted with EtOAc.The combined organic extracts were washed with brine, dried over MgSO₄,filtered and concentrated. The product was purified by flashchromatography (0-5% MeOH/DCM). Yield: 50 mg, 80%. LCMS calculated forC₁₄H₁₆ClN₄O₄S monoisotopic (M+H)⁺: m/z=371.1; found 371.2.

Step 5.6-Acetyl-8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridine-1-carbonitrile

A mixture of6-acetyl-8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridine-1-carboxamide(50 mg, 0.1 mmol) and TEA (200 μL, 1 mmol) in DCM (2 mL) at 0° C. wastreated with trichloroacetyl chloride (60 μL, 0.5 mmol). After 15minutes, the reaction was quenched by the addition of saturated NaHCO₃solution and extracted with DCM. The organic layer was dried over MgSO₄,filtered and concentrated. The product was purified by flashchromatography (0-100% EtOAc in hexanes). Yield: 15 mg, 30%. LCMScalculated for C₁₄H₁₄ClN₄O₃S monoisotopic (M+H)⁺: m/z=353.0; found353.1.

Step 6.6-(1-Aminoethyl)-8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridine-1-carbonitrile(racemic mixture prepared)

Titanium tetraisopropoxide (40 μL, 0.1 mmol) was added to6-acetyl-8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridine-1-carbonitrile(15 mg, 0.042 mmol) in 2.0 M ammonia in ethanol (2 mL, 4 mmol). Thereaction was heated to 65° C. in a sealed reaction vessel overnight. Thereaction mixture was cooled to 0° C. and sodium borohydride (5 mg, 0.1mmol) was added. After 1 hour, an additional portion of NaBH₄ was addedand the reaction was stirred for another 1 hour. The reaction wasquenched by the addition of 1N NH₄OH, and the solids formed were removedby filtration and washed with acetonitrile. The residue obtained onevaporation of solvent from the filtrate was then partitioned betweenwater and EtOAc. The organic layer was washed with brine, dried overMgSO₄, filtered and concentrated. The product was used without furtherpurification. Yield: 10 mg, 67%. LCMS calculated for C₁₄H₁₇ClN₅O₂Smonoisotopic (M+H)⁺: m/z=354.1; found 354.1.

Step 7.2-Amino-N-{1-[8-chloro-1-cyano-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Using 6-(1-aminoethyl)-8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridine-1-carbonitrile (10mg, 0.03 mmol), the method of Example 26, Step 12 was followed to affordthe title compound. Yield: 2 mg. LCMS calculated for C₂₁H₂₁ClN₉O₃Smonoisotopic (M+H)⁺: m/z=514.1; found 514.1. ¹H NMR (500 MHz, d₆-DMSO) δ8.92 (d, J=1.6 Hz, 1H), 8.91 (s, 1H), 8.57 (dd, J=4.5, 1.6 Hz, 1H), 8.14(d, J=6.7 Hz, 1H), 7.59 (s, 1H), 7.02 (dd, J=6.7, 4.5 Hz, 1H), 5.34 (p,J=6.7 Hz, 1H), 3.99 (m, 1H), 3.87-3.78 (m, 1H), 3.74-3.65 (m, 3H),3.61-3.53 (m, 1H), 1.58 (d, J=7.0 Hz, 3H).

Example 165.2-Amino-N-(1-(8-chloro-1-cyano-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (mixture of four diastereomers prepared)

Step 1.6-Acetyl-8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-1-carbonitrile(racemicmixture prepared)

1-[8-Chloro-1-iodo-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl]ethanonewas prepared from 1-(5,8-dichloroimidazo[1,5-a]pyridin-6-yl)ethanone(Example 130, Step 7) and 2-methylthiomorpholine 1,1-dioxide (Enamine)by the method of Example 162, Step 1 followed by iodination as describedin Example 164, Step 1. A mixture of1-[8-chloro-1-iodo-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl]ethanone(0.050 g, 0.107 mmol) and copper(I) cyanide (0.029 g, 0.321 mmol) in DMF(2 mL) was heated to 130° C. in the microwave for 80 minutes. Uponcooling, water was added and the mixture was extracted with DCM (2×).The combined organic extracts were dried over MgSO₄, filtered andconcentrated. The product was purified by flash chromatography (O-100%EtOAc in hexanes). Yield: 20 mg, 51%. LCMS calculated for C₁₅H₁₆ClN₄O₃Smonoisotopic (M+H)⁺: m/z=367.1; found 367.1.

Step 2.6-(1-Aminoethyl)-8-chloro-5-)2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-1-carbonitrile,HCl salt (mixture offour diastereomers prepared)

Titanium(IV) isopropoxide (0.073 mL, 0.245 mmol) was added to a mixtureof6-acetyl-8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-1-carbonitrile(0.030 g, 0.082 mmol) and racemic 2-methylpropane-2-sulfinamide (0.099g, 0.818 mmol) in cyclopentyl methyl ether (1.90 mL). The mixture washeated overnight at 100° C. in a sealed vial. Upon cooling, the mixturewas diluted with EtOH (1 mL) and treated with sodium borohydride (9.3mg, 0.25 mmol). After stirring for 1 hour, the reaction mixture waspoured into brine, and solids were filtered off. The solids were washedwith EtOAc. Layers of the filtrate were separated, and the organic layerwas dried over MgSO₄, filtered, and concentrated. The product was usedwithout further purification. LCMS calculated for C₁₉H₂₇ClN₅O₃S₂monoisotopic (M+H)⁺: m/z=472.1; found 472.1. 4N HCl in dioxane (2 mL)was added toN-(1-(8-chloro-1-cyano-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl-2-methypropane-2-sulfinamide.The mixture was stirred for 1 hour and volatiles were removed in vacuoto afford product as the HCl salt. Yield: 26 mg, 79%. LCMS calculatedfor C₁₅H₁₉ClN₅O₂S monoisotopic (M+H)⁺: m/z=368.1; found 368.1.

Step 3.2-Amino-N-(1-(8-chloro-1-cyano-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (mixture offour diastereomers prepared)

Using6-(1-aminoethyl)-8-chloro-5-)2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-1-carbonitrile,HCl salt (15 mg, 0.037 mmol), Example 26, Step 12 was followed to affordthe title compound. Yield: 4 mg. LCMS calculated for C₂₂H₂₃ClN₉O₃Smonoisotopic (M+H)⁺: m/z=528.1; found 528.1.

Example 166.2-Amino-N-{[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]methyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt

Step 1.8—Chloro-N-methoxy-N-methyl-5-thiomorpholin-4-ylimidazo[1,5-a]pyridine-6-carboxamide

A mixture of5,8-dichloro-N-methoxy-N-methylimidazo[1,5-a]pyridine-6-carboxamide(0.20 g, 0.73 mmol, Example 130, Step 6), thiomorpholine (0.28 mL, 2.9mmol, Aldrich) and N,N-diisopropylethylamine (0.45 mL, 2.6 mmol) inacetonitrile (7 mL) was heated to 120° C. in the microwave for 1.5hours. Volatiles were removed in vacuo and the product was purified byflash chromatography (O-50% EtOAc/hexanes).Yield: 0.23 g, 92%. LCMScalculated for C₁₄H₂₈ClN₄O₂S monoisotopic (M+H)⁺: m/z=341.1; found341.0.

Step 2.8—Chloro-5-thiomorpholin-4-ylimidazo[1,5-a]pyridine-6-carbaldehyde

To8-chloro-N-methoxy-N-methyl-5-thiomorpholin-4-ylimidazo[1,5-a]pyridine-6-carboxamide(0.18 g, 0.53 mmol) in THF (12 mL) at −78° C. was added 1.0 Mdiisobutylaluminum hydride in hexanes (2.1 mL, 2.1 mmol). The mixturewas stirred for 1.5 hours at −78° C., and further 1.0 Mdiisobutylaluminum hydride in hexanes (2.1 mL, 2.1 mmol) was added andthe reaction was continued for 2 hours. The reaction was then quenchedat −78° C. by the dropwise addition of MeOH. Saturated Rochelle saltsolution was added and the mixture was stirred for 30 minutes at roomtemperature. The mixture was then extracted with EtOAc. The extract wasdried over Na₂SO₄, filtered, and concentrated. The product was purifiedby flash chromatography (0-50% EtOAc in hexanes). Yield: 0.091 g, 49%.LCMS calculated for C₁₂H₁₃ClN₃OS monoisotopic (M+H)⁺: m/z=282.0; found282.1.

Step 3.8—Chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridine-6-carbaldehyde

8-Chloro-5-thiomorpholin-4-ylimidazo[1,5-a]pyridine-6-carbaldehyde (91mg, 0.26 mmol) in ethyl acetate (7 mL) was treated withm-chloroperbenzoic acid (89 mg, 0.52 mmol). After stirring for 1 hour,solvent was removed in vacuo. The crude product was dissolved in amixture of MeCN and MeOH and purified by preparative HPLC/MS (pH=10).Yield: 34 mg, 42%. LCMS calculated for C₁₂H₁₃ClN₃O₃S monoisotopic(M+H)⁺: m/z=314.0; found 314.0.

Step 4.1-[8-Chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]methanamine

Titanium tetraisopropoxide (30 μL, 0.1 mmol) was added to a mixture of8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridine-6-carbaldehyde(8.0 mg, 0.025 mmol) in 2.0M ammonia in ethanol (1 mL, 2 mmol). Thereaction was stirred at 65° C. in a sealed reaction vessel for 70minutes. The reaction mixture was cooled to 0° C., and sodiumborohydride (3 mg, 0.08 mmol) was added and the reaction stirred at 0°C. for 30 minutes. A small amount of 1N NH₄OH solution was added,followed by acetonitrile (5 mL). Precipitated solids were removed byfiltration and washed with acetonitrile. The filtrate was concentratedto afford crude product as a solid that was slurried in 10% IPA in DCM(50 mL). The solid product was obtained by filtration. Yield: 7.9 mg,98%. LCMS calculated for C₁₂H₁₆ClN₄O₂S monoisotopic (M+H)⁺: m/z=315.1;found 315.0.

Step 5.2-Amino-N-{[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]methyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt

Using1-[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]methanamine(7.9 mg, 0.025 mmol), the procedure of Example 26, Step 12 was followedto afford the title compound. Yield: 5.1 mg. LCMS calculated forC₁₉H₂₀ClN₈O₃S monoisotopic (M+H)⁺: m/z=475.1; found 475.1. ¹H NMR (400MHz, d₆-DMSO) δ 9.09 (s, 1H), 8.92 (dd, J=6.7, 1.5 Hz, 1H), 8.52 (dd,J=4.5, 1.5 Hz, 1H), 8.29 (t, J=6.0 Hz, 1H), 7.81 (s, 1H), 7.15 (s, 1H),7.01 (dd, J=6.7, 4.5 Hz, 1H), 4.58 (d, J=6.0 Hz, 2H), 3.83-3.67 (m, 4H),3.67-3.53 (m, 2H), 3.40-3.28 (m, 2H).

Example 167.2-Amino-N-((8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.8-Chloro-N-methoxy-N-methyl-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-6-carboxamide(racemicmixture prepared)

A mixture of5,8-dichloro-N-methoxy-N-methylimidazo[1,5-a]pyridine-6-carboxamide(150. mg, 0.547 mmol, Example 130, Step 6), 2-methylthiomorpholine1,1-dioxide HCl salt (203 mg, 1.09 mmol, Enamine) andN,N-diisopropylethylamine (0.191 mL, 1.094 mmol) in acetonitrile (3.0mL) was heated in the microwave to 170° C. for 12 hours. Solvent wasremoved in vacuo and the product was purified by flash chromatography(0-80-100% EtOAc in hexanes). Yield: 91 mg, 43%. LCMS calculated forC₁₅H₂₀ClN₄O₄S monoisotopic (M+H)⁺: m/z=387.1; found 387.1.

Step 2.8-Chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-6-carbaldehyde(racemicmixture prepared)

8-Chloro-N-methoxy-N-methyl-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-6-carboxamide(20. mg, 0.052 mmol) in THF (1.0 mL) at −78° C. was treated with DIBAL-H(1.0 M in hexanes, 0.310 mL, 0.310 mmol). After 50 minutes at −78° C.,the reaction was quenched by the dropwise addition of water and one gramof Rochelle salt was added. The reaction was warmed to room temperatureand DCM (5 mL) was added. The mixture was stirred for 30 minutes and wasdried by the addition of anhydrous MgSO₄. Acetonitrile was added (5 mL)and the mixture was filtered through Celite®. The filtrate wasconcentrated to afford product which was used without furtherpurification. Yield: 13.3 mg, 78%. LCMS calculated for C₁₃H₁₅ClN₃O₃Smonoisotopic (M+H)⁺: m/z=328.0; found 328.1.

Step 3.2-Amino-N-((8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Using8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-6-carbaldehyde(13 mg, 0.040 mmol), Example 166, Steps 4 and 5 were followed to affordthe title compound. Yield: 4.8 mg. LCMS calculated for C₂₀H₂₂ClN₈O₃Smonoisotopic (M+H)⁺: m/z=489.1; found 489.2.

Example 168

Example 168 in Table 16 was prepared by the method of Example 167. NMRdata of the compound of Table 16 is provided in Table 16a.

TABLE 16

Ex. No. Name R = LCMS 168 2-Amino-N-((8-chloro-5-(2,2-dimethyl-1,1-dioxidothiomorpholino)imidazo- [1,5-a]pyridin-6-yl)methyl)pyrazolo-[1,5-a]pyrimidine-3-carboxamide trifluoroacetate salt

Calculated for C₂₁H₂₄ClN₈O₃S monoisotopic (M + H)⁺: m/z = 503.1; found:503.1

TABLE 16a Ex. No. ¹H NMR 168 ¹H NMR (400 MHz, d₆-DMSO) δ 9.00-8.83 (m,1H), 8.50 (dd, J = 4.5, 1.5 Hz, 1H), 8.28 (t, J = 5.9 Hz, 1H), 7.77 (s,1H), 7.13 (s, 1H), 7.01 (dd, J = 6.7, 4.5 Hz, 1H), 4.70 (dd, J = 14.9,6.2 Hz, 1H), 4.53 (dd, J = 14.9, 5.8 Hz, 1H), 4.02-3.90 (m, 1H), 3.81-3.62 (m, 3H), 3.58-3.48 (m, 1H), 3.41-3.28 (m, 1H), 1.52 (s, 3H), 1.35(s, 3H)

Example 169.2-Amino-N-((1,8-dichloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.1,8-Dichloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-6-carbaldehyde(racemic mixture prepared)

8-Chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-6-carbaldehyde(27 mg, 0.082 mmol, Example 167, Step 2) in DMF (1.0 mL) was treatedwith N-chlorosuccinimide (12. mg, 0.091 mmol) at 60° C. for 20 minutes.Upon cooling to room temperature, water was added and the solution wasmade basic by the addition of saturated NaHCO₃ solution (1 mL). SolidNaCl was added and stirred for 10 minutes. The precipitated product, ayellow solid, was isolated by filtration. The product was used withoutfurther purification. Yield: 14 mg, 47%. LCMS calculated forC₁₃H₁₄Cl₂N₃O₃S monoisotopic (M+H)⁺: m/z=362.0; found 362.0.

Step 2.2-Amino-N-((1,8-dichloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Using1,8-dichloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-6-carbaldehyde(racemic) (20 mg, 0.039 mmol), Example 166, Steps 4 and 5 were followedto afford the title compound. Yield: 6.3 mg. LCMS calculated forC₂₀H₂₁Cl₂N₈O₃S monoisotopic (M+H)⁺: m/z=523.1; found 523.0.

Example 170

Example 170 in Table 17 was prepared by the method of Example 169. NMRdata of the compound of Table 17 is shown in Table 17a.

TABLE 17

Ex. No. Name R = LCMS 170 2-Amino-N-((1,8-dichloro-5-(2,2-dimethyl-1,1-dioxidothiomorph- olino)imidazo[1,5-a]pyridin-6-yl)-methyl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide trifluoroacetate salt

Calculated for C₂₁H₂₃Cl₂N₈O₃S monoisotopic (M + H)⁺: m/z = 537.1: found:537.1

TABLE 17a Ex. No. ¹H NMR 170 ¹H NMR (400 MHz, d₆-DMSO) δ 8.95-8.87 (m,1H), 8.59 (s, 1H), 8.54-8.45 (m, 1H), 8.25 (t, J = 5.9 Hz, 1H), 7.02 (s,1H), 7.01-6.98 (m, 1H), 6.52 (br s, 2H), 4.63 (dd, J = 14.9, 6.3 Hz,1H), 4.48 (dd, J = 15.0, 5.7 Hz, 1H), 4.04-3.94 (m, 1H), 3.79- 3.46 (m,5H), 1.52 (s, 3H), 1.31 (s, 3H)

Example 171.2-Amino-N-((8-chloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt

Step 1.8-Chloro-N-methoxy-N-methyl-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridine-6-carboxamide

To 5,8-dichloro-N-methoxy-N-methylimidazo[1,5-a]pyridine-6-carboxamide(50 mg, 0.182 mmol, Example 130, Step 6) and cesium carbonate (178 mg,0.547 mmol) in acetonitrile (5 mL) was added pyrrolidine (14.27 mg,0.201 mmol). The reaction was heated to 70° C. for 2 hours. Upon coolingto room temperature, the reaction mixture was partitioned between waterand EtOAc. The layers were separated and the organic layer was washedwith brine, dried over MgSO₄, filtered, and concentrated. The productwas purified by flash chromatography (0-100% EtOAc in hexanes).Yield: 45mg, 80%. LCMS calculated for C₁₄H₁₈ClN₄O₂ monoisotopic (M+H)⁺:m/z=309.1; found 309.1.

Step 2.8—Chloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridine-6-carbaldehyde

To8-chloro-N-methoxy-N-methyl-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridine-6-carboxamide(45 mg, 0.146 mmol) in THF (1.0 mL) at −78° C. was added DIBAL-H (1.0Min hexanes, 0.874 mL, 0.874 mmol). After stirring for 50 minutes at −78°C., the reaction was quenched by the dropwise addition of water and onegram of Rochelle salt was added. The cooling bath was removed and DCM (5mL) was added. The mixture was stirred for 30 minutes, anhydrous MgSO₄was added. The mixture was diluted with acetonitrile (5 mL) and filteredthrough Celite®. The filtrate was concentrated and the product was usedwithout further purification. Theoretical yield was assumed. LCMScalculated for C₁₂H₁₃ClN₃O monoisotopic (M+H)⁺: m/z=250.1; found 250.1.

Step 3.(8-Chloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6-yl)methanamine

Titanium(IV) isopropoxide (0.213 mL, 0.721 mmol) was added to a solutionof 8-chloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridine-6-carbaldehyde(0.036 g, 0.146 mmol) in 2.0 M ammonia in ethanol (2 mL, 4.00 mmol). Themixture was heated to 65° C. in a sealed vial for 40 minutes. Thereaction mixture was cooled to 0° C. and sodium borohydride (0.020 g,0.541 mmol) was added. After 30 minutes at 0° C., the reaction wasquenched by the addition of 1N NH₄OH solution. Acetonitrile (5 mL) wasadded and solids were removed by filtration. The product (contained inthe filtrate) was purified by preparative HPLC/MS (pH=10). Yield: 20 mg,48%. LCMS calculated for C₁₂H₁₆ClN₄ monoisotopic (M+H)⁺: m/z=251.1;found 251.1.

Step 4.2-Amino-N-((8-chloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt

Using(8-chloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6-yl)methanamine (20mg, 0.07 mmol), the method of Example 26, Step 12 was used to afford thetitle product. Yield: 5 mg. LCMS calculated for C₁₉H₂₀ClN₈O monoisotopic(M+H)⁺: m/z=411.1; found 411.1. ¹H NMR (400 MHz, d₆-DMSO) δ 8.90 (dd,J=6.7, 1.5 Hz, 1H), 8.55 (s, 1H), 8.48 (dd, J=4.5, 1.6 Hz, 1H), 8.17 (t,J=5.9 Hz, 1H), 7.65 (s, 1H), 7.07 (s, 1H), 6.98 (dd, J=6.7, 4.5 Hz, 1H),4.51 (d, J=6.0 Hz, 2H), 3.36 (t, J=6.2 Hz, 4H), 2.08 (t, J=6.2 Hz, 4H).

Example 172.2-Amino-N-((1,8-dichloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetatesalt

Step 1.1,8-Dichloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridine-6-carbaldehyde

A mixture of8-chloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridine-6-carbaldehyde (0.050g, 0.200 mmol, Example 171, Step 2) in DMF (3 mL) was treated withN-chlorosuccinimide (0.027 g, 0.200 mmol) at 60° C. for 3 hours. Uponcooling, the reaction mixture was partitioned between water and EtOAc.The organic extract was washed with brine, dried over MgSO₄, filteredand concentrated. The product was purified by flash chromatography(0-100% EtOAc in hexanes). Yield: 40 mg, 70%. LCMS calculated forC₁₂H₁₂Cl₂N₃O monoisotopic (M+H)⁺: m/z=284.0; found 284.1.

Step 2.N-((1,8-Dichloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6-yl)methyl)-2-methylpropane-2-sulfinamide

Titanium(IV) isopropoxide (0.063 mL, 0.211 mmol) was added to a mixtureof 1,8-dichloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridine-6-carbaldehyde(0.020 g, 0.070 mmol) and (racemic) 2-methylpropane-2-sulfinamide (0.085g, 0.704 mmol) in cyclopentyl methyl ether (3 mL) and the reaction washeated to 60° C. for 1 hour in a sealed vial. Upon cooling to roomtemperature, ethanol (1.0 mL) and sodium borohydride (8.0 mg, 0.21 mmol)were added and the reaction was stirred for 30 minutes. The reactionmixture was poured into saturated NaCl solution and the mixture was thenfiltered. The filter was washed with EtOAc. The layers of the filtratewere separated and the aqueous layer was extracted with EtOAc. Thecombined organic solutions were dried over MgSO₄, filtered andconcentrated. The product was purified by flash chromatography (0-100%EtOAc in hexanes). Yield: 20. mg, 73%. LCMS calculated for C₁₆H₂₃Cl₂N₄OSmonoisotopic (M+H)⁺: m/z=389.1; found 389.1.

Step 3.(1,8-Dichloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6-yl)methanamine,HCl salt

4N HCl in dioxane (1 mL, 4.0 mmol) was added to a mixture ofN-((1,8-dichloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6-yl)methyl)-2-methylpropane-2-sulfinamide(30 mg, 0.077 mmol) in MeOH (1 mL). After 1 hour, solvents were removedin vacuo and the residue was purified by preparative HPLC/MS (pH=10).Yield: 20 mg, 81% yield. LCMS calculated for C₁₂H₁₅Cl₂N₄ monoisotopic(M+H)⁺: m/z=285.1; found 285.1.

Step 4.2-Amino-N-((8-chloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt

Using(1,8-dichloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6-yl)methanamine,HCl salt (20 mg, 0.06 mmol), Example 26, Step 12 was followed to affordthe title compound. Yield: 10 mg. LCMS calculated for C₁₉H₁₉Cl₂N₈Omonoisotopic (M+H)⁺: m/z=445.1; found 445.1. ¹H NMR (400 MHz, d₆-DMSO) δ8.93-8.86 (m, 1H), 8.52-8.42 (m, 1H), 8.27 (s, 1H), 8.16 (t, J=5.8 Hz,1H), 7.00 (s, 1H), 6.98 (dd, J=6.1, 4.1 Hz, 1H), 4.47 (d, J=5.9 Hz, 2H),3.50-3.18 (m, 4H), 2.12-1.94 (m, 4H).

Example 173.2-Amino-N-((8-chloro-1-cyano-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt

Step 1.8-Chloro-1-iodo-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridine-6-carbaldehyde

A mixture of8-chloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridine-6-carbaldehyde (0.050g, 0.200 mmol, from Example 171, Step 2) and N-iodosuccinimide (0.050 g,0.220 mmol) in DMF (3 mL) was stirred for 3 hours at room temperature.The reaction mixture was partitioned between water and EtOAc. Theorganic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. The product was purified by flash chromatography (0-100%EtOAc in hexanes). Yield: 50. mg, 67%. LCMS calculated for C₁₂H₁₂ClIN₃Omonoisotopic (M+H)⁺: m/z=376.0; found 376.0.

Step 2.8-Chloro-6-formyl-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridine-1-carbonitrile

A mixture of8-chloro-1-iodo-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridine-6-carbaldehyde(0.050 g, 0.13 mmol) and copper(I) cyanide (0.036 g, 0.399 mmol) in DMF(2 mL) was heated to 130° C. in the microwave for 80 minutes. Uponcooling, water was added and the mixture was extracted with DCM twice.The combined organic extracts were dried over MgSO₄, filtered, andconcentrated. The product was used without further purification. LCMScalculated for C₁₃H₁₂ClN₄O monoisotopic (M+H)⁺: m/z=275.1; found 275.1.

Step 3.2-Amino-N-((8-chloro-1-cyano-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt

Starting with8-chloro-6-formyl-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridine-1-carbonitrile(0.02 g, 0.073 mmol), Steps 2 through 4 of Example 172 were followed toafford the title compound. Yield: 5 mg. LCMS calculated forC20I⁻119C1N90 monoisotopic (M+H)⁺: m/z=436.1; found 436.1.

Example 174.2-Amino-N-((8-chloro-1-cyano-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.8-Chloro-6-formyl-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-1-carbonitrile(racemic mixture prepared)

Using8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-6-carbaldehyde(racemic, Example 167, Step 2), Steps 1 and 2 of Example 173 werefollowed to afford the title compound. LCMS calculated for C₁₄H₁₄ClN₄O₃Smonoisotopic (M+H)⁺: m/z=353.0; found 353.0.

Step 2.2-Amino-N-((8-chloro-1-cyano-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt(racemic mixture prepared)

Using8-chloro-6-formyl-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-1-carbonitrile(28 mg, 0.079 mmol), Steps 2 through 4 of Example 172 were followed toafford the title compound. LCMS calculated for C₂₁H₂₁ClNO₃S monoisotopic(M+H)⁺: m/z=514.1; found 514.2.

Example 175.2-Amino-N-(1-(8-chloro-1-cyano-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (mixture of four diastereomers prepared)

Step 1.N-((8-Chloro-1-cyano-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)methylene)-2-methylpropane-2-sulfinamide(mixtureof diastereomers prepared)

To a mixture of8-chloro-6-formyl-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-1-carbonitrile(28 mg, 0.079 mmol, Example 174, Step 1) and2-methylpropane-2-sulfinamide (19.24 mg, 0.159 mmol, racemic) in THF(2.0 mL) was added titanium(IV) isopropoxide (0.070 mL, 0.24 mmol). Themixture was stirred at 70° C. in a sealed vial for 50 minutes. Themixture was cooled to 0° C. and was treated with water (0.50 mL). Themixture was then diluted with 5 mL each of acetonitrile and EtOAc. Afterstirring for 10 minutes, Na₂SO₄ was added. The mixture was stirred for 5minutes and was filtered through Celite®. The filter aid was washed withadditional EtOAc and the filtrate was concentrated to afford crudeproduct. The product was purified by flash chromatography (0-100% EtOAcin hexanes). Yield: 32 mg, 88%. LCMS calculated for C₁₈H₂₃ClN₅O₃S₂monoisotopic (M+H)⁺: m/z=456.1; found 456.0.

Step 2.6-(1-Aminopropyl)-8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-1-carbonitrile(mixture offour diastereomers prepared)

N-((8-Chloro-1-cyano-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)methylene)-2-methylpropane-2-sulfinamide(20 mg, 0.044 mmol) in THF (2.0 mL) at 0° C. was treated withethylmagnesium chloride (2.0 M in ether, 0.175 mL, 0.351 mmol). Thecooling bath was removed and the reaction was allowed to warm to roomtemperature and stir for 10 minutes at room temperature. The reactionmixture was then re-cooled to 0° C. and MeOH (0.5 mL) was added. 4.0 MHCl in dioxane (0.44 mL, 1.8 mmol) was introduced. The reaction mixturewas warmed to room temperature and stirred for 30 minutes. Solvent wasremoved in vacuo and the product was purified by preparative HPLC/MS(pH=10). Yield: 12.6 mg, 75%. LCMS calculated for C₁₆H₂₁ClN₅O₂Smonoisotopic (M+H)⁺: m/z=382.1; found 382.1.

Step 3.2-Amino-N-(1-(8-chloro-1-cyano-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (mixture offour diastereomers prepared)

Using6-(1-aminopropyl)-8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-1-carbonitrile(mixture of diastereomers) (12.6 mg, 0.033 mmol), the method of Example26, Step 12 was followed to afford the title compound. Yield: 13.7 mg.LCMS calculated for C₂₃H₂₅ClN₉O₃S monoisotopic (M+H)⁺: m/z=542.1, found542.2.

Example 176

Example 176 in Table 18 was prepared by the method of Example 175, usingcyclopropylmagnesium bromide in Step 2.

TABLE 18

Ex. No. Name R = LCMS 1762-Amino-N-{(8-chloro-1-cyano-5-(2-methyl-1,1-dioxido-thiomorpholino)imidazo[1,5-a]pyridin-6-yl)(cyclopropyl)-methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoro- acetate salt(mixture of four diastereomers prepared)

Calculated for C₂₄H₂₅ClN₉O₃S monoisotopic (M + H)⁺: m/z = 554.1; found:554.1

Example 177.2-Amino-N-(1-(8-chloro-1-cyano-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (mixture of four diastereomers prepared)

Step 1.6-(1-Amino-2,2,2-trilluoroethyl)-8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-1-carbonitrile(mixture offour diastereomers prepared)

To N-((8-chloro-1-cyano-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)methylene)-2-methylpropane-2-sulfinamide (22. mg,0.048 mmol, Example 175, Step 1) and tetramethylammonium fluoride (5.39mg, 0.058 mmol, Aldrich) in DMF (1.0 mL) at 0° C. was addedtrimethyl(trifluoromethyl)silane (0.018 mL, 0.121 mmol, Aldrich). Themixture was stirred at 0° C. for 2 hours. Additionaltrimethyl(trifluoromethyl)silane (23 mg, 0.18 mmol) was addedportionwise as the reaction stirred for a further 1 hour and 20 minutesat 0° C. Saturated NH4C1 solution was added and the mixture wasextracted with EtOAc. The combined extracts were washed with brine,dried over Na₂SO₄, filtered, and concentrated. The residue was dissolvedin MeOH (1.0 mL), cooled to 0° C. and 4.0 M HCl in dioxane (0.36 mL, 1.4mmol) was added. After 15 minutes, volatiles were removed in vacuo. Theresidue was dissolved in MeOH and triethylamine was added to neutralize.Volatiles were again removed in vacuo. The product was then purified byflash chromatography (0-5% MeOH in DCM).Yield: 5.7 mg, 28%. LCMScalculated for C₁₅H₁₆ClF₃N₅O₂S monoisotopic (M+H)⁺: m/z=422.1; found422.1.

Step 2.2-Amino-N-(1-(8-chloro-1-cyano-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)-2,2,2-trilluoroethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (mixture offour diastereomers prepared)

Using6-(1-amino-2,2,2-trifluoroethyl)-8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridine-1-carbonitrile(5.7 mg, 0.014 mmol), the method of Example 26, Step 12 was followed toafford the title compound. Yield: 3.8 mg. LCMS calculated forC₂₂H₂₀ClF₃N₉O₃S monoisotopic (M+H)⁺: m/z=582.1; found 582.1.

Example 178.2-Amino-N-{1-[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]propyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.1-(8-Chloro-5-thiomorpholin-4-ylimidazo[1,5-a]pyridin-6-yl)butan-1-one

2.0 M Propylmagnesium chloride in diethyl ether (0.14 mL, 0.29 mmol) wasadded to a solution of8-chloro-N-methoxy-N-methyl-5-thiomorpholin-4-ylimidazo[1,5-a]pyridine-6-carboxamide(33 mg, 0.097 mmol, Example 166, Step 1) in THF at 0° C. The reactionwas stirred for one hour at 0° C. and then allowed to stir with warmingto room temperature for 2 hours. The reaction was re-cooled to 0° C. andquenched by the addition of 1.0 M HCl (0.3 mL). The solution was stirredfor 15 minutes. Saturated NaHCO₃ was added to ensure basicity, and themixture was extracted with EtOAc three times. The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The product was purified by flash chromatography (0-50%EtOAc in hexanes). Yield: 12 mg, 38%. LCMS calculated for C₁₅H₁₉ClN₃OSmonoisotopic (M+H)⁺: m/z=324.1; found 324.1.

Step 2.1-[8-Chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]butan-1-one

1-(8—Chloro-5-thiomorpholin-4-ylimidazo[1,5-a]pyridin-6-yl)butan-1-one(11 mg, 0.035 mmol) in ethyl acetate (1 mL) was treated withm-chloroperbenzoic acid (18 mg, 0.11 mmol). The reaction was stirred for1 hour and solvent was removed in vacuo. The product was purified bypreparative HPLC/MS (pH=10) and eluent evaporated. Yield: 6.0 mg, 48%.LCMS calculated for C₁₅H₁₉ClN₃O₃S monoisotopic (M+H)⁺: m/z=356.1, found356.1.

Step 3.1-[8—Chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]butan-1-amine(racemicmixture prepared)

Sodium cyanoborohydride (7.6 mg, 0.12 mmol) was added to a mixture of1-[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]butan-1-one(6.0 mg, 0.017 mmol) and ammonium acetate (28 mg, 0.36 mmol) in MeOH(0.75 mL). The mixture was sealed and heated to 70° C. for 2 days.Additional ammonium acetate (28 mg, 0.36 mmol) and sodiumcyanoborohydride (7.6 mg, 0.12 mmol) were added and heating wascontinued for 2 days. Upon cooling to room temperature, saturated NaHCO3was added. The mixture was diluted with water and the aqueous mixturewas saturated with NaCl. The aqueous mixture was extracted with 10%iPrOH in DCM three times. The combined extracts were dried over Na₂SO₄,filtered and concentrated. The product was used without furtherpurification. LCMS calculated for C₁₅H₂₂ClN₄O₂S monoisotopic (M+H)⁺:m/z=357.1, found 357.1.

Step 4.2-Amino-N-{1-[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]propyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Using1-[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]butan-1-amine,the method of Example 26, Step 12 was followed to provide the titlecompound. Yield: 3.1 mg. LCMS calculated for C₂₂H₂₆ClN₈O₃S monoisotopic(M+H)⁺: m/z=517.2, found 517.1. ¹H NMR (400 MHz, d₆-DMSO) δ 9.01 (s,1H), 8.91 (dd, J=6.7, 1.5 Hz, 1H), 8.57 (dd, J=4.5, 1.5 Hz, 1H), 8.10(d, J=7.4 Hz, 1H), 7.74 (s, 1H), 7.21 (s, 1H), 7.01 (dd, J=6.7, 4.6 Hz,1H), 5.34-5.26 (m, 1H), 4.01-3.21 (m, 8H), 2.07-1.91 (m, 1H), 1.79-1.68(m, 1H), 1.58-1.44 (m, 1H), 1.43-1.27 (m, 1H), 0.96 (t, J=7.2 Hz, 3H).

Example 179

Example 179 in Table 19 was prepared by the method of Example 178, usingethylmagnesium chloride in Step 1. NMR data for the compounds of Table19 is shown in Table 19a.

TABLE 19

Ex. No. Name R = LCMS 179 2-Amino-N-{1-[8-chloro-5-(1,1-dioxido-thiomorpholin-4-yl)imidazo[1,5-a]- pyridin-6-yl]propyl}pyrazolo[1,5-a]-pyrimidine-3-carboxamide trifluoro-

Calculated for C₂₁H₂₄ClN₈O₃S monoisotopic (M + H)⁺: m/z = 503.1: found:503.1 acetate salt (racemic mixture prepared)

TABLE 19a Ex. No. ¹H NMR 179 ¹H NMR (400 MHz, CD₃OD) δ 9.50 (s, 1H),8.69 (dd, J = 6.8, 1.6 Hz, 1H), 8.56 (dd, J = 4.5, 1.6 Hz, 1H), 8.09 (s,1H), 7.40 (s, 1H), 6.98 (dd, J = 6.8, 4.5 Hz, 1H), 5.35 (dd, J = 8.9,6.1 Hz, 1H), 4.21-4.09 (m, 1H), 3.99-3.81 (m, 2H), 3.81-3.69 (m, 1H),3.67- 3.31 (m, 4H), 2.14-2.02 (m, 1H), 1.99-1.86 (m, 1H), 1.14 (t, J =7.4 Hz, 3H)

Example 180.2-Amino-N-{1-[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl]imidazo[1,5-a]pyridin-6-yl]-2,2,2-trifluoroethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.N-{(1E)-[8-Chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]methylene}-2-methylpropane-2-sulfinamide

The method of Example 175, Step 1 was used, starting with8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridine-6-carbaldehyde(20 mg, 0.064 mmol, Example 166, Step 3) to afford the title compound.Yield: 20 mg, 75%. LCMS calculated for C₁₆H₂₂ClN₄O₃S₂ monoisotopic(M+H)⁺: m/z=417.1; found 417.1.

Step 2.148—Chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl1-2,2,2-trilluoroethanamine(racemicmixture prepared)

N-{(1E)-[8—Chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]methylene}-2-methylpropane-2-sulfinamide(10. mg, 0.024 mmol) in THF (1.5 mL) at −45° C., was treated withtetramethylammonium fluoride (2.4 mg, 0.026 mmol, Aldrich), followed by(trifluoromethyl)trimethylsilane (4.6 μL, 0.031 mmol, Aldrich) in THF(0.10 mL). The mixture was then allowed to warm to −20° C., andadditional (trifluoromethyl)trimethylsilane (4.6 μL, 0.031 mmol) in THF(0.1 mL) was added. The solution was warmed to 0° C. and further(trifluoromethyl)trimethylsilane (4.6 μL, 0.031 mmol) andtetramethylammonium fluoride (2.4 mg, 0.026 mmol), were added. After 30minutes of stirring at 0° C., 1N HCl (0.5 mL) was added. Volatiles wereremoved in vacuo. The residue was dissolved in MeOH (1.0 mL) and treatedwith 4.0 M HCl in dioxane (0.18 mL, 0.72 mmol) at 0° C. for 15 minutes.Volatiles were removed in vacuo and the product was purified bypreparative HPLC/MS (pH=10). Yield: 2.0 mg, 22%. LCMS calculated forCoH₁₅ClF₃N₄O₂S monoisotopic (M+H)⁺: m/z=383.1; found 383.0.

Step 3.2-Amino-N-{1-[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]-2,2,2-trilluoroethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

1-[8-Chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]-2,2,2-trifluoroethanamine(2.0 mg, 0.0052 mmol) was treated according to the method of Example 26,Step 12 to afford the title compound. Yield: 1.2 mg. LCMS calculated forC₂₀H₁₉ClF₃N₈O₃S monoisotopic (M+H)⁺: m/z=543.1; found 543.1. ¹H NMR (400MHz, CD₃OD) 6 9.46 (s, 1H), 8.93 (d, J=8.7 Hz, 1H), 8.73 (dd, J=6.8, 1.5Hz, 1H), 8.60 (dd, J=4.5, 1.5 Hz, 1H), 8.12 (s, 1H), 7.36 (s, 1H), 7.02(dd, J=6.8, 4.6 Hz, 1H), 6.70-6.54 (m, 1H), 4.13-3.31 (m, 8H).

Example 181.2-Amino-N-(1-(8-chloro-5-(1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)-2-methylpropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1.4-(6-(1-Amino-2-methylpropyl)-8-chloroimidazo[1,5-a]pyridin-5-yl)thiomorpholine1,1-dioxide

Using(E)-N-((8-chloro-5-(1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)methylene)-2-methylpropane-2-sulfinamide(45 mg, 0.11 mmol, Example 180, Step 1), the method of Example 175, Step2 was followed, using isopropylmagnesium chloride (2.0 M in THF, 0.43mL, 0.86 mmol) to afford the title compound. Yield: 4.0 mg, 10%. LCMScalculated for C₁₅H₂₂ClN₄O₂monoisotopic (M+H)⁺: m/z=357.1; found 357.1.

Step 2.2-Amino-N-(1-(8-chloro-5-(1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)-2-methylpropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrilluoroacetatesalt (racemic mixture prepared)

Using4-(6-(1-amino-2-methylpropyl)-8-chloroimidazo[1,5-a]pyridin-5-yl)thiomorpholine1,1-dioxide (4.0 mg, 0.011 mmol), the method of Example 26, Step 12 wasfollowed to afford the title compound. Yield: 3.6 mg. LCMS calculatedfor C₂₂H₂₆ClN₈O₃S monoisotopic (M+H)⁺: m/z=517.2; found 517.2. ¹H NMR(400 MHz, d₆-DMSO) δ 8.92 (dd, J=6.7, 1.5 Hz, 1H), 8.86 (s, 1H), 8.57(dd, J=4.5, 1.5 Hz, 1H), 8.17 (d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.16 (s,1H), 7.01 (dd, J=6.7, 4.5 Hz, 1H), 5.12 (t, J=8.6 Hz, 1H), 3.94-3.25 (m,8H), 2.27-2.14 (m, 1H), 1.15 (d, J=6.4 Hz, 3H), 0.87 (d, J=6.7 Hz, 3H).

Example 182 Example 182 in Table 20 was prepared by the method ofExample 181, using cyclopropylmagnesium bromide in Step 1. NMR data forthe compound of Table 20 is shown in Table 20a.

TABLE 20

Ex. No. Name R = LCMS 182 2-Amino-N-((8-chloro-5-(1,1-dioxido-thiomorpholino)imidazo[1,5-a]pyridin-6-yl)(cyclopropyl)methyl)pyrazolo[1,5-a]- pyrimidine-3-carboxamidetrifluoro- acetate salt (racemic mixture prepared)

Calculated for C₂₂H₂₄ClN₈O₃S monoisotopic (M + H)⁺: m/z = 515.1;found:515.1

TABLE 20a Ex. No. ¹H NMR 182 ¹H NMR (400 MHz, d₆-DMSO) δ 8.95 (s, 1H),8.93 (dd, J = 6.7, 1.5 Hz, 1H), 8.57 (dd, J = 4.5, 1.5 Hz, 1H), 8.20 (d,J = 7.2 Hz, 1H), 7.77 (s, 1H), 7.31 (s, 1H), 7.02 (dd, J = 6.7, 4.5 Hz,1H), 4.91 (t, J = 7.7 Hz, 1H), 3.95-3.66 (m, 3H), 3.62-3.38 (m, 4H),3.38- 3.21 (m, 1H), 1.56-1.43 (m, 1H), 0.74-0.61 (m, 2H), 0.60-0.45 (m,1H), 0.37-0.22 (m, 1H)

Example 183.2-Amino-N-[1-(8-chloro-5-cyclohexylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1. 1-(8-Chloro-5-cyclohexylimidazo[1,5-a]pyridin-6-yl)ethanone

To a degassed solution of1-(5,8-dichloroimidazo[1,5-a]pyridin-6-ypethanone (10.0 mg, 0.0436 mmol,Example 130, Step 7) in 1,4-dioxane (2 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex withdichloromethane (1:1) (2 mg, 0.002 mmol) and 0.4 M dicyclohexylzinc inether (0.2 mL, 0.08 mmol). The resulting mixture was heated to 50° C.for 1 hour. Additional[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (2 mg) and 0.4 M dicyclohexylzinc in ether(0.2 mL) were added and the reaction was heated to 60° C. overnight.Upon cooling, water was added and the mixture was extracted with EtOAc.The organic extract was washed with brine, dried over MgSO₄, filteredand concentrated. The product was purified by flash chromatography(0-60% EtOAc in hexanes). Yield: 10 mg, 80%. LCMS calculated forC₁₅H₁₈ClN₂O monoisotopic (M+H)⁺: m/z=277.1; found 277.1.

Step 2. 1-(8-Chloro-5-cyclohexylimidazo[1,5-a]pyridin-6-yl)ethanaminetrifluoroacetate salt (racemic mixture prepared)

2.0 M Ammonia in ethanol (2 mL, 4 mmol) and titanium tetraisopropoxide(50 μL, 0.2 mmol) were added to1-(8-chloro-5-cyclohexylimidazo[1,5-a]pyridin-6-ypethanone (12 mg, 0.043mmol). The mixture heated to 65° C. overnight in a sealed vial. Aftercooling to room temperature, sodium borohydride (3 mg, 0.07 mmol) wasadded and the reaction was stirred for 1 hour. IN NH₄OH was introducedand the mixture was diluted with acetonitrile. The precipitate thatformed was removed by filtration. The filtrate was collected andacetonitrile was removed in vacuo. The residue was partitioned betweenwater and EtOAc. The aqueous layer was extracted again with EtOAc. Thecombined organic extracts were washed with brine, dried over MgSO₄,filtered, and concentrated. The product was purified by preparativeHPLC/MS (pH=2). Yield: 5 mg. LCMS calculated for C₁₅H₂₁ClN₃ monoisotopic(M+H)⁺: m/z=278.1; found 278.1.

Step 3.2-Amino-N-[1-(8-chloro-5-cyclohexylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

1-(8-Chloro-5-cyclohexylimidazo[1,5-a]pyridin-6-yl)ethanaminetrifluoroacetate salt (5 mg, 0.02 mmol) was treated by the method ofExample 26, Step 12 to afford the title compound. Yield: 3 mg. LCMScalculated for C₂₂H₂₅ClN₇O monoisotopic (M+H)⁺: m/z=438.2; found 438.1.

Example 184.2-Amino-N-[1-(8-chloro-3-methyl-5-phenyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

Step 1. Methyl 5-chloro-2-phenylnicotinate

A degassed mixture of methyl 2,5-dichloronicotinate (4.25 g, 20.6 mmol),phenylboronic acid (2.77 g, 22.7 mmol, Aldrich), K₂CO₃ (6.13 g, 44.4mmol) and bis(triphenylphosphine)palladium(II) chloride (1.6 g, 2.3mmol) in water (15 mL) and 1,4-dioxane (40 mL) was heated to 80° C.overnight. Upon cooling, the reaction mixture was diluted with EtOAc andwater and filtered through Celite®. The aqueous layer was separated andextracted with two further portions of EtOAc. The combined organicextracts were washed with water and brine, dried over Na₂SO₄, filteredand concentrated. The product was purified by flash chromatography(0-80% EtOAc in hexanes). Yield: 3.9 g, 76%. LCMS calculated for C₁₃H₁₁ClNO₂ monoisotopic (M+H)⁺: m/z=248.0; found 248.0.

Step 2. Methyl 5-chloro-2-phenylnicotinate 1-oxide

Methyl 5-chloro-2-phenylnicotinate (3.9 g, 16 mmol) in ethaneperoxoicacid (8.1 mL, 38 mmol) was heated to 90° C. for 3.5 hours. Additionalethaneperoxoic acid (16.0 mL, 76 mmol) was added portionwise at 1 hourincrements over 4 hours. Solvent was removed in vacuo and the productwas purified by flash chromatography (0-50% EtOAc/hexanes). Yield: 2.74g, 66%. LCMS calculated for C₁₃H₁₁ClNO₃ monoisotopic (M+H)⁺: m/z=264.0;found 264.0.

Step 3. Methyl 5,6-dichloro-2-phenylnicotinate

Methyl 5-chloro-2-phenylnicotinate 1-oxide (2.74 g, 10.4 mmol) inphosphoryl chloride (27 mL, 290 mmol) was heated to 90° C. for 1.5hours. The POCl3 was evaporated on the rotovap and the residue wassubjected to flash chromatography (0-30% EtOAc/hexanes). Yield: 2.20 g,75.0%. LCMS calculated for C₁₃H₁₀Cl₂NO₂ monoisotopic (M+H)⁺: m/z=282.0;found 282.0.

Step 4. Methyl8-chloro-3-methyl-5-phenyl[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate

A mixture of methyl 5,6-dichloro-2-phenylnicotinate (0.500 g, 1.77 mmol)and hydrazine hydrate (0.10 mL, 2.0 mmol) in ethanol (5 mL) was heatedto 75° C. for 1 hour. Further hydrazine hydrate (0.10 mL, 2.0 mmol) wasadded and heating was continued for 3.5 hours. Additional hydrazinehydrate (0.1 mL) was added and the heating was continued for 45 minutes,then discontinued and the reaction mixture was stirred at roomtemperature overnight. Volatiles were removed in vacuo and the productwas used without further purification in triazole form. Triethylorthoacetate (5 mL, 30 mmol) was added to the residue and the reactionwas heated to 85° C. for 1 hour. Volatiles were again removed in vacuoto afford a solid that was used without further purification.Theoretical yield assumed. LCMS calculated for C₁₅H₁₃ClN₃O₂ monoisotopic(M+H)⁺: m/z=302.1; found 302.1.

Step 5. 8-Chloro-3-methyl-5-phenyl[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid

Methyl8-chloro-3-methyl-5-phenyl[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate(0.524 g, 1.74 mmol) in methanol (10 mL) was treated with 3.0 M NaOH(2.3 mL, 7.0 mmol). After stirring for 20 minutes, 1N HCl was added toachieve pH=4. The solid white product precipitated and was isolated byfiltration and air dried. Yield: 0.36 g, 72%. LCMS calculated forC₁₄H₁₁ClN₃O₂ monoisotopic (M+H)⁺: m/z=288.1; found 288.0.

Step 6.2-Amino-N-[1-(8-chloro-3-methyl-5-phenyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared) Using8-chloro-3-methyl-5-phenyl[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid, the methods described in Steps 9-12 of Example 26 were followed toafford the title compound. LCMS calculated for C₂₂H₂₀ClN₈₀ monoisotopic(M+H)⁺: m/z=447.1; found 447.1. ¹ H NMR (400 MHz, CD₃OD) 6 8.68 (dd,J=6.8, 1.6 Hz, 1H), 8.53 (dd, J=4.5, 1.6 Hz, 1H), 7.89-7.84 (m, 1H),7.83 (s, 1H), 7.71-7.47 (m, 4H), 6.97 (dd, J=6.8, 4.5 Hz, 1H), 4.79 (q,J=7.2 Hz, 1H), 1.93 (s, 3H), 1.48 (d, J=7.0 Hz, 3H). Example 185.2-Amino-N-[1-(8-chloro-5-phenyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate salt (racemic mixture prepared)

The title compound was prepared by the method of Example 184,substituting trimethyl orthoformate for triethyl orthoacetate in Step 4.LCMS calculated for C₂₁H₁₈ClN₈O monoisotopic (M+H)⁺: m/z=433.1; found433.1. ¹H NMR (400 MHz, CD₃OD) δ 8.68 (dd, J=6.8, 1.6 Hz, 1H), 8.57 (s,1H), 8.53 (dd, J=4.5, 1.6 Hz, 1H), 7.92-7.86 (m, 1H), 7.85 (s, 1H),7.73-7.51 (m, 4H), 6.97 (dd, J=6.8, 4.5 Hz, 1H), 4.97 (q, J=6.9 Hz, 1H),1.52 (d, J=7.0 Hz, 3H).

Example A. THP-1 RPS6 ELISA Assay

To measure the Phosphorylated Ribosomal Protein S6 (RPS6) in celllysates, THP-1 cells (Human Acute Monocytic Leukemia) are purchased fromATCC (Manassas, Va.) and maintained in RPMI with 10% FBS (Gibco/LifeTechnologies, Carlsbad, Calif.). For the assay, THP-1 cells are serumstarved overnight in RPMI, then plated in RPMI (2×10⁵ cells/well in 90μL) into 96-well flat-bottom tissue culture treated plates (Corning,Corning, N.Y.), in the presence or absence of a concentration range oftest compounds. Covered plates are incubated for 2 hours at 37° C., 5%CO₂ then treated with or without 10 nM MCP-1(MYBioSource, San Diego,Calif.) for 15 minutes at 37° C., 5% CO₂. Plates are centrifuged at 1600RPM and supernatants are removed. Cells are lysed in Lysis Buffer (CellSignaling, Danvers, Mass.) with Protease Inhibitor (Calbiochem/EMD,Germany), PMSF (Sigma, St Louis Mo.), HALTS (Thermo Fisher, Rockford,Ill.) for 30 min on wet ice. Cell lysates are frozen at −80° C. beforetesting. The lysates are tested in the Human/Mouse/Rat Phospho-RPS6ELISA (R&D Systems, Inc. Minn, Minn.). The plate is measured using amicroplate reader (SpectraMax M5-Molecular Devices, LLC Sunnyvale,Calif.) set to 450 nm with a wavelength correction of 540. IC₅₀determination is performed by fitting the curve of inhibitor percentinhibition versus the log of the inhibitor concentration using theGraphPad Prism 5.0 software.

Example B. PI3K-γ Scintillation Proximity Assay

Materials

[γ-³³P]ATP (10 mCi/mL) and Wheat Germ Agglutinin (WGA) YSi SPAScintillation Beads was purchased from Perkin-Elmer (Waltham, Mass.).Lipid kinase substrate, D-myo-Phosphatidylinositol 4,5-bisphosphate(PtdIns(4,5)P2)D (+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked(PIP2), CAS 204858-53-7, was purchased from Echelon Biosciences (SaltLake City, Utah). PI3Kγ (p110γ) Recombinant Human Protein was purchasedfrom Life technology (Grand Island, N.Y.). ATP, MgCl₂, DTT, EDTA, MOPSand CHAPS were purchased from Sigma-Aldrich (St. Louis, Mo.).

The kinase reaction was conducted in polystyrene 384-well GreinerBio-one white plate from Thermo Fisher Scientific in a final volume of25 μL. Inhibitors were first diluted serially in DMSO and added to theplate wells before the addition of other reaction components. The finalconcentration of DMSO in the assay was 2%. The PI3Kγ assay was carriedout at room temperature in 20 mM MOPS, pH 6.7, 10 mM MgCl₂, 5 mM DTT andCHAPS 0.03%. Reactions were initiated by the addition of ATP, the finalreaction mixture consisted of 20 μM PIP2, 2 μM ATP, 0.5 μCi [γ-³³P] ATP,13 nM PI3Kγ. Reactions were incubated for 120 min and terminated by theaddition of 40 μL SPA beads suspended in quench buffer: 163 mM potassiumphosphate pH 7.8, 20% glycerol, 25 mM EDTA. The final concentration ofSPA beads is 1.0 mg/mL. After the plate sealing, plates were shakenovernight at room temperature and centrifuged at 1500 rpm for 10 min,the radioactivity of the product was determined by scintillationcounting on Topcount (Perkin-Elmer). IC₅₀ determination was performed byfitting the curve of percent of the solvent control activity versus thelog of the inhibitor concentration using the GraphPad Prism 6.0software. Data for the Examples, obtained using the methods described inExample B, are provided in Table B.

Example C. PI3Kδ Scintillation Proximity Assay

Materials

[γ-³³P]ATP (10 mCi/mL) and Wheat Germ Agglutinin (WGA) YSi SPAScintillation Beads was purchased from Perkin-Elmer (Waltham, Mass.).Lipid kinase substrate, D-myo-Phosphatidylinositol 4,5-bisphosphate(PtdIns(4,5)P2)D (+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked(PIP2), CAS 204858-53-7, was purchased from Echelon Biosciences (SaltLake City, Utah). PI3K6(p1106 /p85a) Recombinant Human Protein waspurchased from Eurofins (St Charles, Mo.). ATP, MgCl₂, DTT, EDTA, MOPSand CHAPS were purchased from Sigma-Aldrich (St. Louis, Mo.).

The kinase reaction was conducted in polystyrene 384-well GreinerBio-one white plate from Thermo Fisher Scientific in a final volume of25 μL. Inhibitors were first diluted serially in DMSO and added to theplate wells before the addition of other reaction components. The finalconcentration of DMSO in the assay was 2%. The PI3Kδ assay was carriedout at room temperature in 20 mM MOPS, pH 6.7, 10 mM MgCl₂, 5 mM DTT andCHAPS 0.03%. Reactions were initiated by the addition of ATP, the finalreaction mixture consisted of 20 μM PIP2, 2 μM ATP, 0.5 μCi [γ-³³P] ATP,3.4 nM PI3Kδ. Reactions were incubated for 120 min and terminated by theaddition of 40 μL SPA beads suspended in quench buffer: 163 mM potassiumphosphate pH 7.8, 20% glycerol, 25 mM EDTA. The final concentration ofSPA beads is 1.0 mg/mL. After the plate sealing, plates were shakenovernight at room temperature and centrifuged at 1500 rpm for 10 min,the radioactivity of the product was determined by scintillationcounting on Topcount (Perkin-Elmer). IC₅₀ determination was performed byfitting the curve of percent of the solvent control activity versus thelog of the inhibitor concentration using the GraphPad Prism 6.0software.

Data for the Examples, obtained using the methods described in ExamplesA, B and C, are provided in Table 21.

TABLE 21 PI3Kγ PI3Kδ PI3Kγ_THP1_RPS6_ELISA Ex. No. IC₅₀ (nM) IC₅₀ (nM)IC₅₀ (nM)  1 ++ ++  2 ++ +++  3a + + #  3b ++++ ++++  4 + + #  5 + + # 6 + + #  7 + + #  8 +++ +++  9 ++ ++  10 ++ +++  11 ++ ++  5a +++ +++ 6a +++ +++  7a ++++ ++++  8a +++ ++++  9a +++ ++++  10a +++ ++++  11a+++ ++++  12 ++ ++  13 ++ ++  14 + ++ ##  15 + ++ ###  16 ++ +++  17 +++++  18 ++ +++  19 + + #  20 ++ ++  21 +++ ++++  22 ++ ++  23 + +++ ## 24 + ++  25 ++ +++  26 + + #  27 + +  28 ++ +++  29 + +++  30 ++ ++ 31A + + #  31B + + #  32 + + #  33 + + #  34 + + #  35 + + #  36 + + # 36A + + #  37 + ++ #  38A + + #  38B + + #  39 + + #  40 + + #  41 + +#  42 + + #  43 + + #  44 ++ +++ ###  45 + + #  46 ++ ++  47 ++ ++ 48 + + #  49 + + #  50 + + #  51 +++ ++++ NT  52 + ++ #  53 + +++ ### 54 + + ###  55 + +++ ###  56 + + #  57 + + #  58 + + #  59 + + #  60 +++ #  61 + +++ ##  62 + ++ #  63 ++ ++ #  64 ++ ++  65 + + #  66 + + # 67 + + #  68 + + #  69 + ++ ##  70 + + #  71A + ++ ##  71B + + # 72A + + #  72B + + #  73A + + #  73B + + #  73C-73D ++ ++++  74 + + # 75A + ++ #  75B + + #  76A + + #  76B + ++ #  77A + ++ #  77B + + # 78A + ++ #  78B + + #  79 + ++ ###  80 + ++ #  81 + + #  82 + + # 83 + + #  84 + + #  85 + + #  86 + ++ ###  87 + ++ #  88 + + #  89 + ++#  90A + ++ #  90B + ++ #  91 + + ##  92 + ++ #  93 + +++ ###  94 + ++ # 95 + + ##  96A + + ##  96B + + ###  97 + ++ ##  98 ++ +++ NA  99 ++ +NA 100 + ++ ### 101 + ++ # 102 + ++ ### 103A + ++ ## 103B + ++ # 104 + +# 105 + + # 106 + ++ ### 107 + ++ # 108 + ++ NA 109 + + # 110 + + #111 + + # 112A + + # 112B + + # 113 + + # 114 + + # 115 + + # 116 + + #117 ++ +++ NT 118 + + # 119 + ++ # 120 + + # 121 + ++ # 122 + + #123 + + # 124 ++ ++++ ### 125 + ++ # 126 + +++ # 127 + + # 128 + +++ ###129 + +++ ## 130 + ++ # 131 + + # 132 ++ ++ NT 133 + ++ # 134 + ++ ###135 + ++ ### 136 + ++ ### 137 + + # 138 + ++ ## 139 + + # 140 + + #141 + ++ # 142 + + # 143 + ++ ## 144 + ++ # 145 + + ### 146 + + # 147 +++ # 148 ++ ++ # 149 + + # 150 + + # 151 + + # 152 + + # 153 + + # 154++ ++ ## 155A + ++ # 155B + + # 156 + +++ ## 157 + ++ ## 158 + ++ # 159++ +++ NT 160 + + NT 161 + + NT 162 + ++ # 163 + + # 164 + +++ ### 165 ++++ # 166 + +++ ## 167 + ++ # 168 + +++ ### 169 + ++ # 170 + +++ ###171 + ++ ### 172 + ++ ## 173 ++ +++ ### 174 + +++ ### 175 + +++ # 176 ++++ # 177 + ++++ ## 178 + + # 179 + + # 180 + + # 181 + + # 182 + + #183 ++ +++ NT 184 ++ ++++ NT 185 ++ ++++ NT + refers to IC₅₀ of <100 nM;++ refers to IC₅₀ of <500 nM; +++ refers to an IC₅₀ of <2000 nM; ++++refers to an IC₅₀ of ≥2000 nM. # refers to IC₅₀ of <500 nM; ## refers toIC₅₀ of <1000 nM; ### refers to an IC₅₀ of ≥1000 nM.

Example D: In Vitro JAK Kinase Assay

Compounds herein were tested for inhibitory activity of JAK targetsaccording to the following in vitro assay described in Park et al.,Analytical Biochemistry 1999, 269, 94-104. The catalytic domains ofhuman JAK1 (a.a. 837-1142), JAK2 (a.a. 828-1132) and JAK3 (a.a.781-1124) were expressed using baculovirus in insect cells and purified.The catalytic activity of JAK1, JAK2 or JAK3 was assayed by measuringthe phosphorylation of a biotinylated peptide. The phosphorylatedpeptide was detected by homogenous time resolved fluorescence (HTRF).IC5os of compounds were measured for each kinase in the 40 μL reactionsthat contain the enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8)buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%) BSA. For the 1mM IC₅₀ measurements, ATP concentration in the reactions was 1 mM.Reactions were carried out at room temperature for 1 hour and thenstopped with 20 μL 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20 in assaybuffer (Perkin Elmer, Boston, Mass.). Binding to the Europium labeledantibody took place for 40 minutes and HTRF signal was measured on aPHERA star plate reader (BMG, Cary, N.C.).

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1.-94. (canceled)
 95. A method of treating a disease or disorderassociated with overexpression of PI3Kγ kinase, comprising administeringto a patient in need thereof a therapeutically effective amount of acompound selected from:2-amino-N-(1-[8-chloro-5-(2-methyl-1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-{1-[8-chloro-1-cyano-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(8-chloro-1-cyano-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;and2-amino-N-(1-(8-chloro-1-cyano-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;or a pharmaceutically acceptable salt thereof
 96. The method of claim95, wherein the disease or disorder is an autoimmune disease ordisorder, cancer, cardiovascular disease, or neurodegenerative disease.97. The method of claim 95, wherein the disease or disorder is lungcancer, melanoma, pancreatic cancer, breast cancer, prostate cancer,liver cancer, colon cancer, endometrial cancer, bladder cancer, skincancer, cancer of the uterus, renal cancer, gastric cancer, or sarcoma.98. The method of claim 95, wherein the sarcoma is Askin's tumor,sarcoma botryoides, chondrosarcoma, Ewing's sarcoma, malignanthemangioendothelioma, malignant schwannoma, osteosarcoma, alveolar softpart sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcomaprotuberans, desmoid tumor, desmoplastic small round cell tumor,epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletalosteosarcoma, fibrosarcoma, gastrointestinal stromal tumor,hemangiopericytoma, hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma,liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheralnerve sheath tumor, neurofibrosarcoma, rhabdomyosarcoma, synovialsarcoma, or undifferentiated pleomorphic sarcoma.
 99. The method ofclaim 95, wherein the disease or disorder is acute myeloid leukemia,acute monocytic leukemia, small lymphocytic lymphoma, chroniclymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma,T-cell acute lymphoblastic leukemia, cutaneous T-cell lymphoma, largegranular lymphocytic leukemia, mature peripheral t-cell neoplasm,anaplastic large cell lymphoma, or lymphoblastic lymphoma.
 100. Themethod of claim 99, wherein the mature peripheral t-cell neoplasm isT-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia,aggressive NK-cell leukemia, mycosis fungoides/Sezary syndrome,anaplastic large cell lymphoma, enteropathy type T-cell lymphoma, adultT-cell leukemia/lymphoma, or angioimmunoblastic T-cell lymphoma. 101.The method of claim 99, wherein the anaplastic large cell lymphoma issystemic anaplastic large cell lymphoma or primary cutaneous anaplasticlarge cell lymphoma.
 102. The method of claim 95, wherein the disease ordisorder is Burkitt's lymphoma, acute myeloblastic leukemia, chronicmyeloid leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, hairy cellleukemia, Mantle cell lymphoma, small lymphocytic lymphoma, follicularlymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma,Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acutelymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatictissue lymphoma, mediastinal (thymic) large B-cell lymphoma,lymphomatoid granulomatosis, splenic marginal zone lymphoma, primaryeffusion lymphoma, intravascular large B-cell lymphoma, plasma cellleukemia, extramedullary plasmacytoma, smouldering myeloma, monoclonalgammopathy of undetermined significance, or diffuse large B celllymphoma.
 103. The method of claim 102, wherein the non-Hodgkin'slymphoma is relapsed non-Hodgkin's lymphoma, refractory non-Hodgkin'slymphoma, recurrent follicular non-Hodgkin's lymphoma, indolentnon-Hodgkin's lymphoma, or aggressive non-Hodgkin's lymphoma.
 104. Themethod of claim 102, wherein the diffuse large B cell lymphoma isactivated B-cell like diffuse large B cell lymphoma, or germinal centerB cell diffuse large B cell lymphoma.
 105. The method of claim 102,wherein the Burkitt's lymphoma is endemic Burkitt's lymphoma, sporadicBurkitt's lymphoma, or Burkitt's-like lymphoma.
 106. The method of claim95, wherein the disease or disorder is rheumatoid arthritis, multiplesclerosis, systemic lupus erythematous, asthma, allergy, pancreatitis,psoriasis, anaphylaxis, glomerulonephritis, inflammatory bowel disease,thrombosis, meningitis, encephalitis, diabetic retinopathy, benignprostatic hypertrophy, myasthenia gravis, Sjogren's syndrome,osteoarthritis, or atherosclerosis.
 107. The method of claim 95, whereinthe disease or disorder is autoimmune hemolytic anemia, systemic lupuserythematosus, lupus nephritis, or pemphigus.
 108. The method of claim107, wherein the idiopathic thrombocytopenic purpura is relapsedidiopathic thrombocytopenic purpura or refractory idiopathicthrombocytopenic purpura.
 109. The method of claim 107, wherein thevasculitis is Behcet's disease, Cogan's syndrome, giant cell arteritis,polymyalgia rheumatica, Takayasu's arteritis, Buerger's disease, centralnervous system vasculitis, Kawasaki disease, polyarteritis nodosa,Churg-Strauss syndrome, mixed cryoglobulinemia vasculitis,Henoch-Schönlein purpur, hypersensitivity vasculitis, microscopicpolyangiitis, Wegener's granulomatosis, or anti-neutrophil cytoplasmantibody associated systemic vasculitis.
 110. The method of claim 95,wherein the disease or disorder is Alzheimer's disease, central nervoussystem trauma, or stroke.
 111. The method of claim 95, furthercomprising administering an inhibitor of JAK1, an inhibitor of JAK2, aninhibitor of JAK1/JAK2, or an inhibitor of PI3Kδ, to said patient. 112.The method of claim 95, wherein disease or disorder is lung cancer,melanoma, breast cancer, acute myeloid leukemia, acute monocyticleukemia, chronic myelogenous leukemia, multiple myeloma, acutemyeloblastic leukemia, chronic myeloid leukemia, or smoldering myeloma.113. The method of claim 95, wherein the disease or disorder is lungcancer.
 114. The method of claim 113, wherein the lung cancer isnon-small cell lung cancer.
 115. The method of claim 95, wherein thedisease or disorder is melanoma.
 116. The method of claim 95, whereinthe disease or disorder is breast cancer.
 117. The method of claim 95,wherein the disease or disorder is acute myeloid leukemia, chronicmyelogenous leukemia, multiple myeloma, myelofibrosis, or smolderingmyeloma.
 118. The method of claim 95, wherein the compound is2-amino-N-(-[8-chloro-5-(2-methyl-1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 119. The method of claim118, wherein the compound is2-amino-N-((1S)-1-(8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 120. The method of claim118, wherein the compound is2-amino-N-((S)-1-(8-chloro-5-((R)-2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 121. The method of claim118, wherein the compound is2-amino-N-((S)-1-(8-chloro-5-((S)-2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 122. The method of claim95, wherein the compound is2-amino-N-{1-[8-chloro-1-cyano-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide,or a pharmaceutically acceptable salt thereof. cm
 123. The method ofclaim 95, wherein the compound is2-amino-N-(1-(8-chloro-1-cyano-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 124. The method of claim95, wherein the compound is2-amino-N-(1-(8-chloro-1-cyano-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide,or a pharmaceutically acceptable salt thereof.